Phenethanolamine derivatives

ABSTRACT

The present invention relates to novel compounds of formula (I), 
                         
or a salt, solvate, or physiologically functional derivative thereof, to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed under 35 U.S.C. § 371 as the United StatesNational Phase Application of International Application No.PCT/EP03/04367 filed Apr. 24, 2003, which claims priority to GBApplication Nos. 0209482.9 and 0225027.2 filed Apr. 25, 2002 and Oct.28, 2002, respectively.

The present invention is concerned with phenethanolamine derivatives,processes for their preparation, compositions containing them and theiruse in medicine, particularly in the prophylaxis and treatment ofrespiratory diseases.

Certain phenethanolamine compounds are known in the art as havingselective stimulant action at β₂-adrenoreceptors and therefore havingutility in the treatment of bronchial asthma and related disorders. ThusGB 2 140 800 describes phenethanolamine compounds including4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is nowused clinically in the treatment of such medical conditions.

Although salmeterol and the other commercially availableβ₂-adrenoreceptor agonists are effective bronchodilators, the maximumduration of action is 12 hours, hence twice daily dosing is oftenrequired. There is therefore a clinical need for compounds having potentand selective stimulant action at β₂-adrenoreceptors and having anadvantageous profile of action.

According to the present invention, there is provided a compound offormula (I)

-   or a salt, solvate, or physiologically functional derivative    thereof, wherein:-   m is an integer of from 2 to 4;-   p is an integer of from 1 to 4, preferably 1;-   Z is O or CH₂—-   R¹ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, cyano,    nitro, halo, C₁₋₆haloalkyl, XCO₂R⁸, —XC(O)NR⁷R⁸, —XNR⁶C(O)R⁷,    —XNR⁶C(O)NR⁷R⁸, —XNR⁶C(O)NC(O)NR⁷R⁸, —XNR⁶SO₂R⁷, —XSO₂NR⁹R¹⁰,    —XNR⁶SO₂NR⁹R¹⁰, XSR⁶, XSOR⁶, XSO₂R⁶, —XNR⁷R⁸, —XNR⁶C(O)OR⁷,-   or R¹ is selected from —X-aryl, —X-hetaryl, or —X-(aryloxy), each    optionally substituted by 1 or 2 groups independently selected from    hydroxy, C₁₋₆alkoxy, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁶C(O)R⁷,    SR⁶, SOR⁶, —SO₂R⁶, —SO₂NR⁹R¹⁰, —CO₂R⁸, —NR⁷R⁸, or hetaryl optionally    substituted by 1 or 2 groups independently selected from hydroxy,    C₁₋₆alkoxy, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   X is —(CH₂)_(q)— or C₂₋₆ alkenylene;-   q is an integer from 0 to 6, preferably 0 to 4;

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, aryl, hetaryl, hetaryl(C₁₋₆alkyl)- and aryl(C₁₋₆alkyl)-and R⁶ and R⁷ are each independently optionally substituted by 1 or 2groups independently selected from halo, C₁₋₆alkyl, C₃₋₇ cycloalkyl,C₁₋₆ alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl),—SO₂(aryl), —CO₂H, and —CO₂(C₁₋₄alkyl), —NH₂, —NH(C₁₋₆alkyl),aryl(C₁₋₆-alkyl)-, aryl(C₂₋₆alkenyl)-, aryl(C₂₋₆alkynyl)-,hetaryl(C₁₋₆alkyl)-, —NHSO₂aryl, —NH(hetarylC₁₋₆alkyl), —NHSO₂hetaryl,—NHSO₂(C₁₋₆alkyl), —NHC(O)aryl, or —NHC(O)hetaryl;

-   or where R¹ is —XNR⁶C(O)OR⁷, R⁶ and R⁷ may, together with the    —NC(O)O— portion of the group R¹ to which they are bonded, form a    saturated or unsaturated ring, preferably a 5-, 6-, or 7-membered    ring, for example an oxazolidine ring, such as    oxazolidine-2,4-dione,-   or where R¹ is —XNR⁶C(O)NR⁷R⁸, R⁶ and R⁷ may, together with the    —NC(O)N— portion of the group R¹ to which they are bonded, form a    saturated or unsaturated ring, preferably a 5-, 6-, or 7-membered    ring, for example an imidazolidine ring, such as    imidazolidine-2,4-dione;-   R⁸ is selected from hydrogen, C₁₋₆alkyl and C₃₋₇cycloalkyl;-   or R⁷ and R⁸, together with the nitrogen atom to which they are    bonded, form a 5-, 6- or 7-membered nitrogen-containing ring;-   R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₆alkyl,    C₃₋₇cycloalkyl, CO₂(C₁₋₄alkyl), aryl, hetaryl, hetaryl(C₁₋₆alkyl)-    and aryl(C₁₋₆alkyl)-, or R⁹ and R¹⁰, together with the nitrogen to    which they are bonded, form a 5-, 6-, or 7-membered nitrogen    containing ring;-   and R⁹ and R¹⁰ are each optionally substituted by one or two groups    independently selected from halo, C₁₋₆alkyl, and C₃₋₇cycloalkyl,    C₁₋₆haloalkyl;-   R² is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo,    aryl, aryl(C₁₋₆alkyl)-, C₁₋₆haloalkoxy, and C₁₋₆haloalkyl;-   R³ is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo,    aryl, aryl(C₁₋₆alkyl)-, C₁₋₆haloalkoxy, and C₁₋₆haloalkyl; and-   R⁴ and R⁵ are independently selected from hydrogen and C₁₋₄ alkyl    with the proviso that the total number of carbon atoms in R⁴ and R⁵    is not more than 4.

In the compound of formula (I), the group R¹ is preferably attached tothe para- or meta-position, and more preferably to the meta-positionrelative to the -Z(CH₂)_(p) link.

The groups R² and R³ are each independently preferably attached to theortho- or meta-position, more preferably to the ortho position relativeto the -Z(CH₂)_(p)-link.

In one preferred embodiment R¹ represents a substituent as definedabove, other than hydrogen, most preferably attached to themeta-position relative to the -Z(CH₂)_(p) link, and R² and R³ eachrepresent hydrogen.

In another preferred embodiment R¹ represents hydrogen and R² and R³each represent a substituent as defined above, at least one of which isother than hydrogen, and R² and R³ are each independently attached tothe ortho- or meta-positions relative to the -Z(CH₂)_(p) link. In aparticular embodiment, when R² and R³ each represent halogen they arepreferably attached at the ortho positions.

In a particular embodiment of this invention R¹ is suitably selectedfrom hydrogen, C₁₋₆alkyl, hydroxy, cyano, nitro, halo, C₁₋₆haloalkyl,XCO₂R⁸, —XC(O)NR⁷R⁸, —XNR⁶C(O)R⁷, —XNR⁶C(O)NR⁷R⁸, —XNR⁶C(O)NC(O)NR⁷R⁸,—XNR⁶SO₂R⁷, —XSO₂NR⁹R¹⁰, —XSR6, —XSOR⁶, —XSO₂R⁶, —XNR⁷R⁸, —XNR⁶C(O)OR⁷,

-   or R¹ is selected from —X-aryl, —X-hetaryl, or —X-(aryloxy), each    optionally substituted by 1 or 2 groups independently selected from    hydroxy, C₁₋₆alkoxy, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁶C(O)R⁷,    SR⁶, SOR⁶, —SO₂R⁶, —SO₂NR⁹R¹⁰, —CO₂R⁸, —NR⁷R⁸, or hetaryl optionally    substituted by 1 or 2 groups independently selected from hydroxy,    C₁₋₆alkoxy, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined above, provided that    in this instance neither R⁹ nor R¹⁰ represents —CO₂(C₁₋₄alkyl).

In the compounds of formula (I), the group R¹ is suitably selected fromhydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, cyano, halo, XCO₂R⁸,—XC(O)NR⁷R⁸, —XNR⁶C(O)R⁷, —XNR⁶C(O)NR⁷R⁸, —XNR⁶C(O)NC(O)NR⁷R⁸,—XNR⁶SO₂R⁷, —XSO₂NR⁹R¹⁰, —XNR⁶SO₂NR⁹R¹⁰, XSOR⁶, and —XSO₂R⁶,

-   or R¹ is selected from —X-aryl, optionally substituted by 1 or 2    groups independently selected from hydroxy, C₁₋₆alkoxy, halo,    C₁₋₆alkyl,-   C₁₋₆haloalkyl, —NR⁶C(O)R⁷, SR⁶, SOR⁶, —SO₂R⁶, —SO₂NR⁹R¹⁰, —CO₂R⁸,    —NR⁷R⁸, preferably —CO₂R⁸,-   wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined above.

In a further embodiment the group R¹ is suitably selected from hydrogen,C₁₋₄alkyl, hydroxy, halo, —NR⁶C(O)NR⁷R⁸, and —NR⁶SO₂R⁷ wherein R⁶ and R⁷are as defined above or more suitably wherein R⁶ is hydrogen and R⁷ isselected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, and aryl and isoptionally substituted as described above.

In another embodiment, the group R¹ is preferably selected from hydroxy,—XC(O)NR⁷R⁸, and —XSO₂NR⁹R¹⁰. Most preferably R¹ represents a group—XC(O)NR⁷R⁸. In this embodiment X preferably represents —(CH₂)_(q)—where q is zero.

Where R¹ is —XNR⁶C(O)NR⁷R⁸, R⁶ and R⁷ may, together with the —NC(O)N—portion of the group R¹ to which they are bonded, form a saturated orunsaturated ring, preferably a 5-, 6-, or 7-membered ring, for examplean imidazolidine ring, such as imidazolidine-2,4-dione.

Where R¹ is —XNR⁶C(O)OR⁷, R⁶ and R⁷ may, together with the —NC(O)O—portion of the group R¹ to which they are bonded, form a saturated orunsaturated ring, preferably a 5-, 6-, or 7-membered ring, for examplean oxazolidine ring, such as oxazolidine-2,4-dione.

Where R¹ is —XC(O)NR⁷R⁸ or —XNR⁶C(O)NR⁷R⁸, R⁷ and R⁸ may, together withthe nitrogen to which they are bonded, form a 5-, 6-, or 7-memberednitrogen containing ring.

R⁶ and R⁷ are suitably selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, aryl, and hetaryl, independently optionally substitutedby 1 or 2 groups independently selected from CO₂H, —NH₂, and—NH(C₁₋₆alkyl).

In the compounds of formula (I) wherein the group R¹ is substituted byR⁶ and/or R⁸, R⁶ and/or R⁸ are suitably hydrogen.

In a particular embodiment, R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, hetaryl, hetaryl(C₁₋₆alkyl)-and aryl(C₁₋₆alkyl)-, or R⁹ and R¹⁰, together with the nitrogen to whichthey are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring;

-   and R⁹ and R¹⁰ are each optionally substituted by one or two groups    independently selected from halo, C₁₋₆alkyl, and C₃₋₇cycloalkyl,    C₁₋₆haloalkyl;

In a further embodiment, R⁹ and R¹⁰ are suitably independently selectedfrom hydrogen, C₁₋₆alkyl, —CO₂(C₁₋₄)alkyl and C₃₋₇cycloalkyl.

In the compounds of formula (I), R⁴ and R⁵ are preferably independentlyselected from hydrogen and methyl, more preferably R⁴ and R⁵ are bothhydrogen.

In the compounds of formula (I) R² and R³ preferably each independentlyrepresent hydrogen or halogen

Preferably the moiety

-   is attached to the para position of the ‘central’ phenyl ring,    relative to the —NHCR⁴R⁵CH₂— moiety.

As used herein, the term “hetaryl” means a 5- to 10-memberedheteroaromatic ring or bicyclic ring system which includes 1, 2, or 3heteroatoms independently selected from oxygen, nitrogen and sulphur,such as thienyl, pyridyl, 2,4-dihydroxypyrimidinyl,2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl, or bipyridyl, preferably a5- or 6-membered heteroaromatic ring.

As used herein, the term “aryl” either alone or in the term “aryloxy”means a monocyclic or bicyclic aromatic ring system, such as phenyl,naphthyl, or biphenyl. Preferably the term “aryl” means phenyl.

The term ‘alkyl’ as used herein, either as such or as part of anothergroup, such as ‘alkoxy’ encompasses both straight and branched chains.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

The compounds of formula (I) include an asymmetric centre, namely thecarbon atom of the

-   group. The present invention includes both (S) and (R) enantiomers    either in substantially pure form or admixed in any proportions.    Preferably, the compounds of the invention are in the form of    the (R) enantiomers.

Similarly, where R⁴ and R⁵ are different groups, the carbon atom towhich they are attached is an asymmetric centre and the presentinvention includes both (S) and (R) enantiomers at this centre either insubstantially pure form or admixed in any proportions.

Thus the compounds of formula (I) include all enantiomers anddiastereoisomers as well as mixtures thereof in any proportions.

Preferred compounds of the invention include:

-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}urea;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}dicarbonimidic    diamide;-   4-((1R)-2-{[2-(4-{2-[(3-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;-   2-(Hydroxymethyl)-4-((1R)-1-hydroxy-2-{[2-(4-{2-[(3-methylbenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)phenol;-   4-((1R)-2-{[2-(4-{2-[(3-Chlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;-   4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}acetamide;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}nicotinamide;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-2-furamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzonitrile;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}methanesulfonamide;-   4-{(1R)-2-[(2-{4-[2-)Benzyloxy]ethoxy]phenyl}ethyl)aminol]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-N-phenylurea;-   4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;-   4-{(1R)-2-[((1S)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   4-{(1R)-2-[((1R)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzenesulfonamide;-   3-[(2-{4-[2-(}(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzoic    acid;-   4-((1R)-2-{[2-(4-{2-[(4-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;-   4-((1R)-2-{[2-(4-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;-   N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamide,-   N-(tert-butoxycarbonyl)-N-{3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamide;-   4-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;-   4-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;-   4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-isopropoxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;-   4-((1R)-1-Hydroxy-2-}[2-(4-{2-[(4-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzamide;-   N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;-   N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)    ethyl]phenoxy}ethoxy)methyl]-N-methylbenzenesulfonamide;-   4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenol;-   4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenol;-   2-(Hydroxymethyl)-4-[(1R)-1-hydroxy-2-({2-[4-(4phenylbutoxy)phenyl]ethyl}amino)ethyl]phenol;-   4-{(1R)-1-Hydroxy-2-[(2-{4-[4-(3-hydroxyphenyl)butoxy]phenyl}ethyl)amino]ethyl}-2-(hydroxymethyl)phenol;-   4-((1R)-2-{[2-(4-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;-   4-{(1R)-2-[(2-{4-[4-(2,6-Dichlorophenyl)butoxy]phenyl}ethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzenesulfonamide    N-[3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)phenyl]urea;-   3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzoic    acid;-   3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzonitrile;-   3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzamide;-   3′-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-1,1′-biphenyl-3-carboxylic    acid;-   N-Butyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-pentylbenzamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isobutylbenzamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopentylbenzamide;-   and salts, solvates, and physiologically functional derivatives    thereof.

Particularly preferred compounds of the invention include:

-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;-   N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino)ethyl]phenoxy}ethoxy)methyl]benzamide;-   3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzenesulfonamide;-   3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzamide;-   N-Butyl-3-[(2-[4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-pentylbenzamide;-   3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isobutylbenzamide;    and-   3-[(2-[4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino)ethyl]phenoxy}ethoxy)methyl]-N-isopentylbenzamide;-   and salts, solvates, and physiologically functional derivatives    thereof.

Salts and solvates of compounds of formula (I) which are suitable foruse in medicine are those wherein the counterion or associated solventis pharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counterions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds of formula (I) andtheir pharmaceutically acceptable salts, solvates, and physiologicallyfunctional derivatives.

By the term “physiologically functional derivative” is meant a chemicalderivative of a compound of formula (I) having the same physiologicalfunction as the free compound of formula (I), for example, by beingconvertible in the body thereto. According to the present invention,examples of physiologically functional derivatives include esters.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic,oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,methanesulphonic, ethanesulphonic, arylsulphonic (for examplep-toluenesulphonic, benzenesulphonic, naphthalenesulphonic ornaphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic) and isethionic acids. Pharmaceuticallyacceptable base salts include ammonium salts, alkali metal salts such asthose of sodium and potassium, alkaline earth metal salts such as thoseof calcium and magnesium and salts with organic bases such asdicyclohexyl amine and N-methyl-D-glucamine.

Pharmaceutically acceptable esters of the compounds of formula (I) mayhave a hydroxyl group converted to a C₁₋₆alkyl, aryl, aryl C₁₋₆ alkyl,or amino acid ester.

As mentioned above, the compounds of formulae (I) are selectiveβ₂-adrenoreceptor agonists as demonstrated using functional or reportergene readout from cell lines transfected with human beta-adrenoreceptorsas described below. Compounds according to the present invention alsohave the potential to combine long duration of effect with rapid onsetof action. Furthermore, certain compounds have shown an improvedtherapeutic index in animal models relative to existing long-actingβ₂-agonist bronchodilators. As such, compounds of the invention may besuitable for once-daily administration.

Therefore, compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates, and physiologically functional derivativeshave use in the prophylaxis and treatment of clinical conditions forwhich a selective β₂-adrenoreceptor agonist is indicated. Suchconditions include diseases associated with reversible airwaysobstruction such as asthma, chronic obstructive pulmonary diseases(COPD) (e.g. chronic and wheezy bronchitis, emphysema), respiratorytract infection and upper respiratory tract disease.

Other conditions which may be treated include premature labour,depression, congestive heart failure, skin diseases (e.g. inflammatory,allergic, psoriatic, and proliferative skin diseases), conditions wherelowering peptic acidity is desirable (e.g. peptic and gastriculceration) and muscle wasting disease.

Accordingly, the present invention provides a method for the prophylaxisor treatment of a clinical condition in a mammal, such as a human, forwhich a selective β₂-adrenoreceptor agonist is indicated, whichcomprises administration of a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof. In particular, thepresent invention provides such a method for the prophylaxis ortreatment of a disease associated with reversible airways obstructionsuch as asthma, chronic obstructive pulmonary disease (COPD),respiratory tract infection or upper respiratory tract disease. In afurther aspect the present invention provides such a method for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) or muscle wasting disease.

In the alternative, there is also provided a compound of formula (I), ora pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof for use in medical therapy, particularly,for use in the prophylaxis or treatment of a clinical condition in amammal, such as a human, for which a selective β₂-adrenoreceptor agonistis indicated. In particular, there is provided a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof for the prophylaxis or treatment of adisease associated with reversible airways obstruction such as asthma,chronic obstructive pulmonary disease (COPD), respiratory tractinfection or upper respiratory tract disease. In a further aspect, thereis provided a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) or muscle wasting disease.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof in the manufacture of a medicament for theprophylaxis or treatment of a clinical condition for which a selectiveβ₂-adrenoreceptor agonist is indicated, for example a disease associatedwith reversible airways obstruction such as asthma, chronic obstructivepulmonary disease (COPD), respiratory tract infection or upperrespiratory tract disease. In a further aspect, there is provided acompound of formula (I), or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof in the manufacture of amedicament for the prophylaxis or treatment of a clinical conditionselected from premature labour, depression, congestive heart failure,skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferativeskin diseases), conditions where lowering peptic acidity is desirable(e.g. peptic and gastric ulceration) and muscle wasting disease.

The amount of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof which is required to achieve a therapeutic effect will, ofcourse, vary with the particular compound, the route of administration,the subject under treatment, and the particular disorder or diseasebeing treated. The compounds of the invention may be administered byinhalation at a dose of from 0.0005 mg to 10 mg, preferably 0.005 mg to0.5 mg. The dose range for adult humans is generally from 0.0005 mg to100 mg per day and preferably 0.01 mg to 1 mg per day.

While it is possible for the compound of formula (I), or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to be administered alone, it is preferable to presentit as a pharmaceutical formulation.

Accordingly, the present invention further provides a pharmaceuticalformulation comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof, and a pharmaceutically acceptable carrier or excipient, andoptionally one or more other therapeutic ingredients.

Hereinafter, the term “active ingredient” means a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), inhalation (including fine particle dusts or mistswhich may be generated by means of various types of metered dosepressurised aerosols, nebulisers or insufflators), rectal and topical(including dermal, buccal, sublingual and intraocular) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing the active ingredient into association with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Formulations generally contain a powdermix for inhalation of the compound of the invention and a suitablepowder base (carrier substance) such as lactose or starch. Use oflactose is preferred. Each capsule or cartridge may generally containbetween 20 μg-10 mg of the compound of formula (I) optionally incombination with another therapeutically active ingredient.Alternatively, the compound of the invention may be presented withoutexcipients.

Packaging of the formulation may be suitable for unit dose or multi-dosedelivery. In the case of multi-dose delivery, the formulation can bepre-metered (eg as in Diskus, see GB 2242134, U.S. Pat. No. 5,590,645and U.S. Pat. No. 5,873,360; or Diskhaler, see GB 2178965, 2129691 and2169265, and U.S. Pat. No. 4,627,432, U.S. Pat. No. 4,778,054, U.S. Pat.No. 4,811,731 and US50352377) or metered in use (eg as in Turbuhaler,see EP 69715). The content of U.S. Pat. No. 5,590,645, U.S. Pat. No.5,873,360 U.S. Pat. No. 4,627,432, U.S. Pat. No. 4,778,054, U.S. Pat.No. 4,811,731 and US50352377 is incorporated herein by reference. Anexample of a unit-dose device is Rotahaler (see GB 2064336). The Diskusinhalation device comprises an elongate strip formed from a base sheethaving a plurality of recesses spaced along its length and a lid sheethermetically but peelably sealed thereto to define a plurality ofcontainers, each container having therein an inhalable formulationcontaining a compound of formula (I) preferably combined with lactose.Preferably, the strip is sufficiently flexible to be wound into a roll.The lid sheet and base sheet will preferably have leading end portionswhich are not sealed to one another and at least one of the said leadingend portions is constructed to be attached to a winding means. Also,preferably the hermetic seal between the base and lid sheets extendsover their whole width. The lid sheet may preferably be peeled from thebase sheet in a longitudinal direction from a first end of the said basesheet.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. A metered doseinhaler is generally shown and described in European patent No. 1066073,the content of which is hereby incorporated herein by reference.

Aerosol compositions suitable for inhalation can be either a suspensionor a solution and generally contain the compound of formula (I)optionally in combination with another therapeutically active ingredientand a suitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants egoleic acid or lecithin and cosolvents eg ethanol. Pressurisedformulations will generally be retained in a canister (eg an aluminiumcanister) closed with a valve (eg a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10 μm, preferably 2-5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of theactive ingredient as produced may be size reduced by conventional meanseg by micronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline. When an excipient such as lactose is employed, generally,the particle size of the excipient will be much greater than the inhaledmedicament within the present invention. When the excipient is lactoseit will typically be present as milled lactose, wherein not more than85% of lactose particles will have a MMD of 60-90 μm and not less than15% will have a MMD of less than 15 μm.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Solutions for inhalation by nebulation may be formulated with an aqueousvehicle with the addition of agents such as acid or alkali, buffersalts, isotonicity adjusting agents or antimicrobials. They may besterilised by filtration or heating in an autoclave, or presented as anon-sterile product.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose an acacia.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbefore recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

The compounds and pharmaceutical formulations according to the inventionmay be used in combination with or include one or more other therapeuticagents, for example selected from anti-inflammatory agents,anticholinergic agents (particularly an M₁, M₂, M₁/M₂ or M₃ receptorantagonist), other β₂-adrenoreceptor agonists, antiinfective agents(e.g. antibiotics, antivirals), or antihistamines. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with one or moreother therapeutically active agents, for example selected from ananti-inflammatory agent (for example a corticosteroid or an NSAID), ananticholinergic agent, another β₂-adrenoreceptor agonist, anantiinfective agent (e.g. an antibiotic or an antiviral), or anantihistamine. Preferred are combinations comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with acorticosteroid, and/or an anticholinergic, and/or a PDE-4 inhibitor.Preferred combinations are those comprising one or two other therapeuticagents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,(e.g. as alkali metal or amine salts or as acid addition salts), orprodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g.hydrates) to optimise the activity and/or stability and/or physicalcharacteristics (e.g. solubility) of the therapeutic ingredient. It willbe clear also that where appropriate, the therapeutic ingredients may beused in optically pure form.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-dfluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2α agonists), cytokine antagonists (e.g.chemokine antagonists) or inhibitors of cytokine synthesis. Suitableother β₂-adrenoreceptor agonists include salmeterol (e.g. as thexinafoate), salbutamol (e.g. as the sulphate or the free base),formoterol (e.g. as the fumarate), fenoterol or terbutaline and saltsthereof.

Of particular interest is use of the compound of formula (I) incombination with a phosphodiesterase 4 (PDE4) inhibitor or a mixedPDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in this aspectof the invention may be any compound that is known to inhibit the PDE4enzyme or which is discovered to act as a PDE4 inhibitor, and which areonly PDE4 inhibitors, not compounds which inhibit other members of thePDE family as well as PDE4. Generally it is preferred to use a PDE4inhibitor which has an IC₅₀ ratio of about 0.1 or greater as regards theIC₅₀ for the PDE4 catalytic form which binds rolipram with a highaffinity divided by the IC₅₀ for the form which binds rolipram with alow affinity. For the purposes of this disclosure, the cAMP catalyticsite which binds R and S rolipram with a low affinity is denominated the“low affinity” binding site (LPDE 4) and the other form of thiscatalytic site which binds rolipram with a high affinity is denominatedthe “high affinity” binding site (HPDE 4). This term “HPDE4” should notbe confused with the term “hPDE4” which is used to denote human PDE4.

A method for determining IC₅₀s ratios is set out in U.S. Pat. No.5,998,428 which is incorporated herein in full by reference as thoughset out herein. See also PCT application WO 00/51599 for an anotherdescription of said assay.

The preferred PDE4 inhibitors of use in this invention will be thosecompounds which have a salutary therapeutic ratio, i.e., compounds whichpreferentially inhibit cAMP catalytic activity where the enzyme is inthe form that binds rolipram with a low affinity, thereby reducing theside effects which apparently are linked to inhibiting the form whichbinds rolipram with a high affinity. Another way to state this is thatthe preferred compounds will have an IC₅₀ ratio of about 0.1 or greateras regards the IC₅₀ for the PDE4 catalytic form which binds rolipramwith a high affinity divided by the IC₅₀ for the form which bindsrolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Examples of useful PDE4 inhibitors are:

-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone;-   cis    4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic    acid];-   cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];-   (R)-(+)-ethyl    [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate;    and-   (S)-(−)-ethyl    [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate.

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other compounds of interest include:

Compounds set out in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996; thispatent and the compounds it discloses are incorporated herein in full byreference. The compound of particular interest, which is disclosed inU.S. Pat. No. 5,552,438, iscis4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms;

AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem(Sep. 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9);a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 fromChiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitoridentified as Cl-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (Sep. 19-23, Geneva) 1998] 1998, 12 (Suppl. 28):Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), andT2585.

Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listedin WO01/13953, the disclosure of which is hereby incorporated byreference.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compoundswhich are antagonists of the M₁ and M₂ receptors. Exemplary compoundsinclude the alkaloids of the belladonna plants as illustrated by thelikes of atropine, scopolamine, homatropine, hyoscyamine; thesecompounds are normally administered as a salt, being tertiary amines.These drugs, particularly the salt forms, are readily available from anumber of commercial sources or can be made or prepared from literaturedata via, to wit:

-   Atropine—CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine    sulfate—CAS-5908-99-6; atropine oxide—CAS-4438-22-6 or its HCl    salt—CAS-4574-60-1 and methylatropine nitrate—CAS-52-88-0.-   Homatropine—CAS-87-00-3, hydrobromide salt—CAS-51-56-9,    methylbromide salt—CAS-80-49-9.-   Hyoscyamine (d, l)—CAS-101-31-5, hydrobromide salt—CAS-306-03-6 and    sulfate salt—CAS-683516-1.-   Scopolamine—CAS-51-34-3, hydrobromide salt—CAS-6533-68-2,    methylbromide salt—CAS-155-41-9.

Preferred anticholinergics include ipratropium (e.g. as the bromide),sold under the name Atrovent, oxitropium (e.g. as the bromide) andtiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118, the disclosureof which is hereby incorporated by reference.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. The majority of these inhibitors, mostly first generationantagonists, have a core structure, which can be represented by thefollowing formula:

This generalized structure represents three types of antihistaminesgenerally available: ethanolamines, ethylenediamines, and alkylamines.In addition, other first generation antihistamines include those whichcan be characterized as based on piperizine and phenothiazines. Secondgeneration antagonists, which are non-sedating, have a similarstructure-activity relationship in that they retain the core ethylenegroup (the alkylamines) or mimic the tertiary amine group withpiperizine or piperidine. Exemplary antagonists are as follows:

-   Ethanolamines: carbinoxamine maleate, clemastine fumarate,    diphenylhydramine hydrochloride, and dimenhydrinate.-   Ethylenediamines: pyrilamine amleate, tripelennamine HCl, and    tripelennamine citrate.-   Alkylamines: chlropheniramine and its salts such as the maleate    salt, and acrivastine.-   Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,    cyclizine lactate, meclizine HCl, and cetirizine HCl.-   Piperidines: Astemizole, levocabastine HCl, loratadine or its    descarboethoxy analogue, and terfenadine and fexofenadine    hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

Examples of preferred anti-histamines include methapyrilene andloratadine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with acorticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan antihistamine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor and a corticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with aphysiologically acceptable diluent or carrier represent a further aspectof the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. Appropriate doses of known therapeutic agents will bereadily appreciated by those skilled in the art.

According to a further aspect of the invention, there is provided aprocess for preparing a compound of formula (I), or a salt, solvate, orphysiologically functional derivative thereof which comprises a process(a), (b), (c) or (d) as defined below followed by the following steps inany order:

-   -   (i) optional removal of any protecting groups;    -   (ii) optional separation of an enantiomer from a mixture of        enantiomers;    -   (iii) optional conversion of the product to a corresponding        salt, solvate,    -   (iv) optional conversion of a group R¹, R² and/or R³ to another        group R¹, R² and/or R³,

-   or physiologically functional derivative thereof.

In the following description of synthetic routes, R¹, R², R³, R⁴, R⁵, Z,m and p are as defined for formula (I) and R¹¹, R¹², R¹³ and R¹⁴ are asdefined for formula (II) below unless indicated otherwise.

In one general process (a), a compound of formula (I), may be obtainedby deprotection of a protected intermediate, for example of formula(II):

-   or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, Z, m, and    p are as defined for the compounds of formula (I), and R¹¹, R¹², R¹³    and R¹⁴ are each independently either hydrogen or a protecting group    provided that at least one of R¹¹, R¹², R¹³ and R¹⁴ is a protecting    group.

Suitable protecting groups may be any conventional protecting group suchas those described in “Protective Groups in Organic Synthesis” byTheodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons,1999). Examples of suitable hydroxyl protecting groups represented byR¹¹ and R¹² are esters such as acetate ester, aralkyl groups such asbenzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.Examples of suitable amino protecting groups represented by R¹³ includebenzyl, α-methylbenzyl, diphenylmethyl, triphenylmethyl,benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such astrichloroacetyl or trifluoroacetyl.

As will be appreciated by the person skilled in the art, use of suchprotecting groups may include orthogonal protection of groups in thecompounds of formula (II) to facilitate the selective removal of onegroup in the presence of another, thus enabling selectivefunctionalisation of a single amino or hydroxyl function. For example,the —CH(OH) group may be orthogonally protected as —CH(OR¹⁴) using, forexample, a trialkylsilyl group such as triethylsilyl. A person skilledin the art will also appreciate other orthogonal protection strategies,available by conventional means as described in Theodora W Greene andPeter G M Wuts (see above).

The deprotection to yield a compound of formula (I), may be effectedusing conventional techniques. Thus, for example, when R¹¹, R¹², and/orR¹³ is an aralkyl group, this may be cleaved by hydrogenolysis in thepresence of a metal catalyst (e.g. palladium on charcoal).

When R¹¹ and/or R¹² is tetrahydropyranyl this may be cleaved byhydrolysis under acidic conditions. Acyl groups represented by R¹³ maybe removed by hydrolysis, for example with a base such as sodiumhydroxide, or a group such as trichloroethoxycarbonyl may be removed byreduction with, for example, zinc and acetic acid. Other deprotectionmethods may be found in Theodora W Greene and Peter G M Wuts (seeabove). In a particular embodiment of process (a), R¹¹ and R¹² maytogether represent a protecting group as in the compound of formula(III):

-   or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R¹³, R¹⁴,    Z, m, and p are as defined for the compound of formula (II), and R¹⁵    and R¹⁶ are independently selected from hydrogen, C₁₋₆alkyl, or aryl    or R¹⁵ and R¹⁶ together form a carbocyclic ring eg. containg from 5    to 7 carbon atoms. In a preferred aspect, both R¹⁵ and R¹⁶ are    methyl.

The compound of formula (III) may be converted to a compound of formula(I), by hydrolysis with dilute aqueous acid, for example acetic acid orhydrochloric acid in a suitable solvent or by transketalisation in analcohol, for example ethanol, in the presence of a catalyst such as anacid (for example, toluenesulphonic acid) or a salt (such as pyridiniumtosylate) or a resin-bound sulphonic acid such as SCX-2, at normal orelevated temperature.

It will be appreciated that the protecting groups R¹¹, R¹², R¹³ and R¹⁴(including the cyclised protecting group formed by R¹⁵ and R¹⁶ asdepicted in formula (III) may be removed in a single step orsequentially. The precise order in which protecting groups are removedwill in part depend upon the nature of said groups and will be readilyapparent to the skilled worker. Preferably, when R¹⁵ and R¹⁶ togetherform a protecting group as in formula (III) this protecting group isremoved together with any protecting group on the CH(OH) moiety,followed by removal of R¹³. However, preferably the nitrogen protectinggroup is removed first if deprotection is to be effected using basecatalysis.

Compounds of formulae (II) and (III) wherein R¹³ is hydrogen may beprepared from the corresponding compound of formula (IV):

-   or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R¹¹, R¹²,    Z, m, and p are as defined for the compound of formula (II) or    (III).

The conversion of a compound of formula (IV) to a compound of formula(II) or (III) may be effected by treatment with a base, for example anon-aqueous base, such as potassium trimethylsilanolate, or an aqueousbase such as aqueous sodium hydroxide, in a suitable solvent such astetrahydrofuran.

The compounds of formula (IV) may be prepared by reacting a compound offormula (V):

-   wherein R⁴, R⁵, R¹¹, R¹², Z and m are as defined for the compound of    formula (II) and x is as defined below,-   with a compound of forumla (VI):

-   wherein R¹, R², R³, Z and p are as defined for the compound of    formula (I), L is a leaving group such as halo (typically chloro,    bromo or iodo) or a sulphonate eg. alkylsulphonate (typically    methanesulphonate), and x and y each represent 1 or zero such that    the sum of x and y is 1. When x is 1, Z preferably represents O.

The reaction of formula (V) and formula (VI) is advantageously effectedin the presence of a base such as sodium hydride, or an inorganiccarbonate, for example cesium carbonate or potassium carbonate.

Compounds of formula (VI) are commercially available or may be preparedby methods well known to a person skilled in the art.

Compounds of formula (V) may be prepared by coupling a compound offormula (VlI):

-   or a salt or solvate thereof, wherein R¹¹ and R¹² are as defined for    the compound of formula (V) with a compound of formula (VIII):

-   wherein R⁴, R⁵, Z and m are as defined for the formula (I), x is    zero or 1, L¹ is a leaving group, for example a halo group,    (typically bromo or iodo) or a sulphonate such as an alkyl    sulphonate (typically methanesulphonate) an aryl sulphonate    (typically toluenesulphonate) or a haloalkylsulphonate (typically    trifluoromethane sulphonate), and R¹⁷ is a hydroxyl protecting    group, such as an acyl group. The group R¹⁷ may be removed by    standard methods; alternatively, the R¹⁷ protected compound    corresponding to formula (V) may be utilised directly in the    reaction with formula (VI).

The coupling of a compound of formula (VII) with a compound of formula(VIII) may be effected in the presence of a base, such as a metalhydride, for example sodium hydride, or an inorganic base such as cesiumcarbonate, in an aprotic solvent, for example N,N-dimethylformamide. Theprotecting group R¹⁷ may be removed using standard methods, using eg.potassium trimethylsilanolate or sodium hydroxide. Those skilled in theart will appreciate that when potassium silanolate is employed then itis preferable to use only 1 equivalent and mild reaction conditions(room temperature) as an excess of this reagent and high temperaturewill result in cleavage of the oxazolidinone ring.

Compounds of formula (VII) may be prepared by ring closure of a compoundof formula (IX):

-   wherein R¹¹ and R¹² are as defined for the compound of formula (VII)    and R¹⁸ is C₁₋₆alkyl, for example tert-butyl, or aryl, for example    phenyl. The ring closure may be effected by treatment with a base,    such as a metal hydride, for example sodium hydride, in the presence    of an aprotic solvent, for example, N,N-dimethylformamide.

Compounds of formula (IX) may be prepared from the corresponding ketoneof formula (X):

-   wherein R¹¹ and R¹² and R¹⁸ are as defined for the compound of    formula (IX), by reduction by any suitable method, for example by    treatment with borane, in the presence of a chiral catalyst, such as    CBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.

The compound of formula (X) may be prepared from the correspondinghalide of formula (XI):

-   wherein R¹¹ and R¹² are as defined for the compound of formula (IV)    and Y is a halo, suitably bromo.

The conversion of a compound of formula (XI) to a compound of formula(X) may be effected by reaction with the protected amine HN(COOR¹⁸)₂wherein R¹⁸ is as defined for the compound of formula (X) in thepresence of an inorganic base such as cesium carbonate, followed byselective removal of one of the COOR¹⁸ groups, for example by treatmentwith an acid such as trifluoroacetic acid.

Compounds of formula (XI) may be prepared from the correspondingcompound having free hydroxymethyl and hydroxy substituents (whichitself may be prepared from2-bromo-1-(4-hydroxy)-3-hydroxymethyl-phenethyl)ethanone, thepreparation of which is described in GB2140800, by treatment with2-methoxypropene in acetone in the presence of an acid e.g.p-toluenesulphonic acid in a nitrogen atmosphere or by other standardmethods) by forming the protected groups R¹¹ OCH₂— and R¹²O— wherein R¹¹and R¹² are as defined for the compound of formula (XI). Such methodsare described in DE 3513885 (Glaxo).

Compounds of formula (VIII) may be prepared from a compound of formula(XII):

-   wherein x is zero or 1 and R¹⁹ is a hydroxyl protecting group such    as aralkyl, typically benzyl, by conventional chemistry, for example    by conversion of the hydroxyl group to a mesylate which may itself    be converted to bromo by addition of a salt such as    tetraalkylammonium bromide in a solvent such as acetonitrile,    followed by removal of the protecting group R¹⁹ using standard    conditions eg. hydrogenation in the presence of palladium on    charcoal, and then introduction of R¹⁷, for example by reaction with    an acyl anhydride.

Compounds of formula (XII) wherein x is zero are known in the art or canreadily be prepared by the skilled person using standard methods.

Compounds of formula (XII) wherein x is 1 may be prepared from acorresponding compound wherein x is zero by reaction with an appropriatealkylating agent.

Compounds of formulae (II) or (III) where R¹³ is hydrogen or aprotecting group may also be prepared according to the general methodsdescribed below.

In a further process (b) a compound of formula (I), may be obtained byalkylation of an amine of formula (XIII):

-   wherein R¹¹, R¹², R¹³ and R¹⁴ are each independently either hydrogen    or a protecting group, for example as described hereinabove for    compounds of formula (II) and (III);-   with a compound of formula (XIV):

-   wherein L¹ is a leaving group as herein before defined for the    compound of formula (VIII); followed by removal of any protecting    groups present by conventional methods as described above for the    deprotection of compounds of formula (II) and (III). For speed of    reaction, L¹ is preferably bromo or is converted to bromo in situ,    from the corresponding compound wherein L¹ is methanesulphonate, for    example by addition of tetrabutylammonium bromide to the reaction    mixture. In this process R¹³ is preferably hydrogen.

The compound of formula (I), may be formed directly (when in thecompound of formula (XIII) R¹¹, R¹², R¹³ and R¹⁴ are each hydrogen) orvia a compound of formula (II) or (III) which may or may not be isolated(when in the compound of formula (XIII) at least one of R¹¹, R¹², R¹³and R¹⁴ is a protecting group).

The reaction of compounds of formulae (XIII) and (XIV) is optionallyeffected in the presence of an organic base such as a trialkylamine, forexample, diisopropylethylamine, and in a suitable solvent for exampleN,N-dimethylformamide, or acetonitrile.

Compounds of formula (XIII) are known in the art (for example EP-A0947498) or may be readily prepared by a person skilled in the art, forexample from the corresponding halide of formula (XI) as defined above.The conversion of a compound of formula (XI) to a compound of formula(XIII) may be effected by reaction with sodium azide in a suitablesolvent, for example N,N-dimethylformamide, to give the correspondingcompound wherein Y denotes N₃. The carbonyl group may then be reduced tothe corresponding alcohol by any suitable method, for example bytreatment with borane, in the presence of a chiral catalyst, such as(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole,in a suitable solvent such as tetrahydrofuran. The azide group may bereduced to the corresponding amine group by any suitable method, forexample by catalytic hydrogenation in the presence of a catalyst such aspalladium/charcoal or platinum oxide.

Compounds of formula (XIV) may be prepared by general methods describedhereinabove, as will be evident to a person skilled in the art, forexample using methods similar to those used in the preparation ofcompounds (XII) and the reaction of compounds (V) and (VI).

In a further process (c) a compound of formula (I), may be prepared byreacting a compound of formula (XV):

-   wherein R¹¹, R¹² and R¹⁴ are as hereinbefore defined and L³ is a    leaving group, with an amine of formula (XVI):

-   wherein R¹, R², R³, R⁴, R⁵, Z, m, and p are as defined for the    compounds of formula (I), and R¹³ is either hydrogen or a protecting    group,-   followed by removal of any protecting groups present by conventional    methods as described above for the deprotection of compounds of    formula (II).

The reaction may be effected using conventional conditions for suchdisplacement reactions.

Compounds of formula (XV) may be prepared by methods known in the art.

Compounds of formula (XVI) may be prepared by reacting a compound offormula (XIV) with an amine R¹³NH₂.

According to a further process (d) compounds of formula (I) wherein oneof R⁴ and R⁵ represents alkyl may be prepared by reacting a compound offormula (XIII):

-   as hereinbefore defined,-   with a compound of formula (XVII):

-   wherein R¹, R², R³, R⁴, Z, m, and p are as defined for the compounds    of formula (I), under conditions suitable to effect reductive    amination, for example in the presence of a reducing agent such as a    borohydride, typically tetramethylammonium (triacetoxy) borohydride.

Compounds of formula (XVII) may be prepared by alkylation of a compoundof formula (XVIII)

-   wherein R⁴, Z and m are as defined for formula (I) and x is zero or    1, with a compound of formula (VI) as thereinbefore defined using    methods analogous to those described hereinbefore for the    preparation of compounds of formula (IV).

Compounds of formula (XVIII) wherein x is zero are commericallyavailable or may readily be prepared by conventional methods. Compoundsof formula (XVIII) where x is 1 may be prepared from a correspondingcompound wherein x is zero by appropriate alkylation.

It will be appreciated that at any convenient stage in the preparationof a compound of formula (I) one or more of the substituents R¹, R² andR³ may, if appropriate, be converted into a different substituent.Conveniently such conversion may be effected on a compound of formula(IV) prior to the deprotection stages.

Thus for example a compound wherein R¹ represents NO₂ may be convertedinto a compound wherein R¹ represents —NH₂ for example by hydrogenation,e.g. in the presence of a palladium or platinum catalyst and in asolvent such as an alcohol. A compound wherein R¹ represents —NH₂ may beconverted into a compound wherein R¹ represents XN R⁶C(O)N R⁷ R⁸ byreaction with an appropriate isocyanate or into a compound wherein R¹represents L-XN R⁶(CO)N(CO)N R⁷ R⁸ using excess isocyanate—similarly,amide and sulfonamide derivatives may be formed by reaction with anappropriate acyl or sulfonyl chloride or anhydride. Alternatively asimple amide substituent may be prepared from the corresponding nitrile,by treatment with a base such as potassium trimethylsilanolate.

To prepare a compound wherein R¹ represents SR⁶, SOR⁶ or SO₂R⁶ acompound wherein R¹ represents halo, e.g.iodo may be reacted with anappropriate mercaptan R⁶SH in the presence of 1,1′bis-(diphenylphosphino)ferrocene, tris(dibenzylideneacetone)di-palladium, N-methylpyrrolidinone and an organic base such astriethylamine. The sulfide product initially obtained from this reactionmay if desired be oxidised to give the corresponding compound wherein R¹represents a group SOR⁶. Oxidation may be carried out using conventionaloxidising agents, for example sodium periodate, in a suitable solvent,for example an alcohol such as ethanol.

When R¹ represents SOR⁶ the product may initially be obtained as amixture of diastereoisomers. These may be separated by conventionalmethods, for example using chiral chromatography, such as chiral HPLC.Alternatively the sulphoxides can be prepared selectively in one of thediastereomeric forms by the use of a chiral oxidising agent.

A compound wherein R¹ represents SO₂R⁶ may be prepared by oxidation of acorresponding compound wherein R¹ represents SOR⁶ or SR⁶ by reactionwith a peracid, for example metachlorperbenzoic acid. When a sulfide (ieR¹ represents SR⁶) is employed as the starting material, the peracidshould be used in excess, to ensure complete oxidation.

To prepare a compound wherein R¹ represents phenyl or substituted phenyla compound wherein R¹ represents halo, e.g.iodo may be reacted with anappropriate arylboronic acid or arylboronic acid ester in the presenceof a catalyst system such as palladium, for example,tetrakis(triphenylphosphine) palladium (0) orbis(diphenylphosphino)ferrocene palladium dichloride with a base such assodium carbonate or caesium carbonate, in a suitable solvent for example1,2-dimethoxyethane, or N,N-dimethylformamide.

Other transformations will be apparent to those skilled in the art, andmay be effected by conventional reactions.

It will be appreciated that in any of the routes (a) to (d) describedabove, the precise order of the synthetic steps by which the variousgroups and moieties are introduced into the molecule may be varied. Itwill be within the skill of the practitioner in the art to ensure thatgroups or moieties introduced at one stage of the process will not beaffected by subsequent transformations and reactions, and to select theorder of synthetic steps accordingly.

The enantiomeric compounds of the invention may be obtained (i) byseparation of the components of the corresponding racemic mixture, forexample, by means of a chiral chromatography column, enzymic resolutionmethods, or preparing and separating suitable diastereoisomers, or (ii)by direct synthesis from the appropriate chiral intermediates by themethods described above.

Optional conversions of a compound of formula (I), to a correspondingsalt may conveniently be effected by reaction with the appropriate acidor base. Optional conversion of a compound of formula (I), to acorresponding solvate or physiologically functional derivative may beeffected by methods known to those skilled in the art.

According to a further aspect, the present invention provides novelintermediates for the preparation of compounds of formula (I), forexample compounds of formula (II), (III), (IV) or (V).

For a better understanding of the invention, the following Examples aregiven by way of illustration.

SYNTHETIC EXAMPLES

Throughout the examples, the following abbreviations are used:

-   LCMS: Liquid Chromatography Mass Spectrometry-   HPLC: High Performance Liquid Chromatography-   RT: retention time-   DCM: dichloromethane-   EtOAc: ethyl acetate-   EtOH: ethanol-   DMAP: N,N-Dimethylaminopyridine-   DMF: N,N-Dimethylformamide-   MeOH: methanol-   THF: tetrahydrofuran-   h: hour(s)-   min: minute(s)

All temperatures are given in degrees centigrade.

Flash silica gel refers to Merck Art No. 9385; silica gel refers toMerck Art No. 7734 Biotage refers to prepacked silica gel cartridgescontaining KP-Sil run on flash 12i chromatography module.

Solid Phase Extraction (SPE) columns are pre-packed cartridges used inparallel purifications, normally under vacuum. These are commerciallyavailable from Varian. SCX cartridges are Ion Exchange SPE columns wherethe stationary phase is polymeric benzene sulfonic acid. These are usedto isolate amines.

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solvent A)and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0.0-7min 0% B, 0.7-4.2 min 100% B, 4.2-5.3min 100% B, 5.3-5.5 min 0% B at a flow rate of 3 mL/min. The massspectra were recorded on a Fisons VG Platform spectrometer usingelectrospray positive and negative mode (ES+ve and ES−ve).

Preparative mass directed HPLC was conducted on a Waters FractionLynxsystem comprising of a Waters 600 pump with extended pump heads, Waters2700 autosampler, Waters 996 diode array and Gilson 202 fractioncollector on a 10 cm×2.54 cm ID ABZ+column, eluting with 0.1% formicacid in water (solvent A) and 0.1% formic acid in acetonitrile (solventB), using the following elution gradient: 0.0-1.0 min 15% B, 1.0-10.0min 55% B, 10.0-14.5 min 99% B, 14.5-14.9 min 99% B, 14.9-15.0 min 15%Bat a flow rate of 20 ml/min and detecting at 200-320 nm at roomtemperature. Mass spectra were recorded on Micromass ZMD massspectrometer using electrospray positive and negative mode, alternatescans. The software used was MassLynx 3.5 with OpenLynx and FractionLynxoptions.

EXAMPLE 1N-{3-[(2-[4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenox]ethoxy)methyl]phenyl}ureaacetate

i) 2-{4-[2-(Benzyloxy)ethoxy]phenyl}ethul methanesulfonate

A solution of 2-{4-[2-(benzyloxy)ethoxy]phenyl}ethanol (JP 10152460) (5g) in DCM (35 mL) was cooled to 0° C. under nitrogen. This was treatedwith N,N-diisopropylethylamine (6.4 mL) and methanesulfonyl chloride(1.6 mL) and stirred at this temperature for 1 h. The solution was thenconcentrated in vacuo, and the residue was taken up in EtOAc and washedwith 2M HCl, NaHCO₃, and brine. The combined organic layers were dried(MgSO₄) and concentrated in vacuo to give the title compound (6.33 g).LCMS RT=3.33 min.

ii) 1-[2-(Benzyloxy)ethoxy]-4-(2-bromoethyl)benzene

A mixture of 2-{4-[2-(benzyloxy)ethoxy]phenyl}ethyl methanesulfonate(6.33 g) and tetrabutylammonium bromide (11.6 g) in acetonitrile (35 mL)was heated at 50° C. under nitrogen for 6 h. The mixture was thenconcentrated in vacuo, and the residue was taken up in EtOAc and washedwith water and brine. The combined organic layers were dried (MgSO₄) andconcentrated in vacuo to give the title compound (5.23 g). LCMS RT=3.79min.

iii) 2-[4-(2-Bromoethyl)phenoxy]ethanol

1-[2-(benzyloxy)ethoxy]-4-(2-bromoethyl)benzene in EtOAc (150 mL) andEtOH (50 mL) was hydrogenated over 10% Pd/C (530 mg) at room temperatureand atmospheric pressure for 8 h. The catalyst was removed by filtrationover Celite, washed with EtOAc and concentrated in vacuo to give thetitle compound (3.6 g). LCMS RT=2.82 min.

iv) 2-[4-(2-Bromoethyl)phenoxy]ethyl acetate

A mixture of 2-[4-(2-bromoethyl)phenoxy]ethanol (900 mg), aceticanhydride (0.5 mL), triethylamine (1.0 mL) and DMAP (13 mg) in DCM (5mL) was stirred at room temperature for 0.5 h. The reaction was quenchedby pouring into aq. NaHCO₃ and the organic layer was washed with 2M HCl,dried (MgSO₄) and concentrated in vacuo to give the title compound (1.03g). LCMS RT=3.32 min.

v) Di(tert-butyl)2-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate

Cesium carbonate (70.4 g) was added to a stirred suspension of2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone, (Glaxo, DE3513885, 1985) (61.8 g) and di-t-butyl iminodicarboxylate (47.15 g) inacetonitrile (600 ml) under nitrogen. After vigorous stirring at 21° for24 h the mixture was diluted with water (ca800 ml) and the product wasextracted with diethyl ether (1 litre, then 200 ml). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated toca400 ml. The white crystals were collected by filtration, washed withdiethyl ether and dried to give the title compound (24.4 g) δ (CDCl₃)7.78 (1H, dd, J 8, 2 Hz), 7.65 (1H, brs), 6.87 (1H, d, J 8 Hz), 4.97(2H,s), 4.88 (2H, s), 1.56 (6H, s) and 1.48 (18H, s). Further concentrationof the mother liquors gave additional product (13.8 g). A third crop(7.1 g) was obtained by chromatographing the mother liquors on silicagel, evaporating the appropriate eluate and triturating with diethylether.

vi) tert-Butyl2-(2.2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylcarbamate

Trifluoroacetic acid (92 ml) was added to a stirred solution ofdi(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate,(352.55 g) in dichloromethane (3.6 litres) at 21° and the reaction wasstirred for 1.5 h. Aqueous NaOH solution (1.75 litres) was added andafter 10 min the phases were separated. The organic layer was washedwith water, dried (MgSO₄) and evaporated to an oil. This was storedunder high vacuum overnight and then triturated with hexane:ether (3:1)to give the crude product (226.61 g). This was purified byrecrystallisation from diethyl ether to give the title compound (122.78g). Further product (61.5 g) was obtained from the mother liquors byevaporation and chromatography on a Biotage using 15% ethyl acetate inhexane. LCMS RT=3.37 min.

vii) tert-Butyl(2R)-2-(2.2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate

A 2M solution of borane—dimethyl sulphide in THF (28 ml) was addedslowly to a 1M solution of(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolein toluene (56 ml) at 0° under nitrogen. A solution of tert-butyl2-(2,2-dimethyl-4H1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2 g)in THF (1.3 litres) was added slowly keeping the temperature below 5°followed by 2M solution of borane—dimethyl sulphide in THF (252 ml) over50 min. After 1 h, 2M HCl (170 ml) was added with cooling and themixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated NaHCO₃ solution and brine and dried(MgSO₄). The solution was concentrated and the product purified bychromatography on flash silica gel (800 g), eluting successively withhexane:ethyl acetate (4:1 then 3:1) to give the title compound (93.3 g),LCMS RT=3.31 min.

viii) (5R)-5-(2.2-Dimethyl-4H-1.3-benzodioxin-6-yl)-1.3-oxazolidin-2-one

tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate,(86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension ofsodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with coolingsuch that the internal temperature remained at 0° under nitrogen. Themixture was stirred at 21° for 2 h. The mixture was recooled to 0° and2M HCl (134 ml) was added. The mixture was diluted with water and theproduct was extracted with ethyl acetate twice. The solution was washedwith brine twice, dried (MgSO₄) and evaporated to give the titlecompound (63.55 g) LCMS RT=2.66 min.

ix)2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethylacetate

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (651mg) in DMF (15 mL) was treated with sodium hydride (84 mg) undernitrogen and stirred for 1 h. A solution of2-[4-(2-bromoethyl)phenoxy]ethyl acetate (500 mg) in DMF (5 mL) wasadded and the reaction mixture was stirred for a further 2 h. This wasthen concentrated in vacuo and the residue was taken up in EtOAc, washedwith water, brine and dried (MgSO₄). The solution was concentrated invacuo and the residue was purified by chromatography (Biotage, 90 g)eluting with cyclohexane-EtOAc (2:1) to give the title compound (355mg). LCMS RT=3.26 min.

x)(5R)-5-(2,2-Dimethyl-4H-1.3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenvl]ethyl}-1,3-oxazolidin-2-one

2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethylacetate (3.7 g) in THF (100 mL) was treated with KOSiMe₃ (1.39 g) andstirred at room temperature for 3 h. The solution was then poured intophosphate buffer (pH 6.5) and water, extracted with EtOAc, dried (MgSO₄)and concentrated in vacuo to give the title compound (3.31 g). LCMSRT=2.91 min.

xi)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-nitrobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one(1 g) in DMF (15 mL) was treated with sodium hydride (167 mg) undernitrogen and stirred for 15 min. To this was added 3-nitrobenzyl bromide(721 mg) and the reaction mixture was stirred for 20 h. The solution wasthen concentrated in vacuo and the residue was taken up in EtOAc, washedwith water and brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by chromatography (Biotage, 40 g) eluting withCH₂Cl₂-MeOH (500:1) and then CH₂Cl₂-MeOH (250:1) to give the titlecompound (1.22 g). LCMS RT=3.57 min.

xii)(5R)-3-[2-(4-{2-[(3-Aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-nitrobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one(1.22 g) in EtOAc (20 mL) and EtOH (15 mL) was hydrogenated over PtO₂(122 mg) at room temperature and atmospheric pressure for 3 h. Thecatalyst was then removed by filtration over Celite, washed with EtOAcand concentrated in vacuo to give the title compound (994 mg). LCMSRT=3.23 min.

xiii)N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)ureaandN-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)dicarbonimidicdiamide

A mixture of(5R)-3-[2-(4-[2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(100 mg) and acetic acid (0.1 mL) in THF (1 mL) was treated with asuspension of sodium cyanate (25 mg) in water and stirred at roomtemperature for 4 h. The solution was diluted in EtOAc, washed withNaHCO₃, brine and concentrated in vacuo to give a mixture ofN-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)ureaandN-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)dicarbonimidicdiamide as a 72:28 ratio respectively. LCMS RT=3.15 min and 3.27 min.

xiv)N-[3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]ureaandN-[3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]dicarbonimidicdiamide

The mixture ofN-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)ureaandN-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)dicarbonimidicdiamide (135 mg) in THF (2 mL) was treated with KOSiMe₃ (123 mg) and theresulting solution was heated at 75° C. under nitrogen for 1.5 h. Thereaction mixture was then quenched with MeOH and concentrated in vacuo.The residue was taken up in EtOAc, washed with water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by HPLC to giveN-[3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]urea(12 mg). LCMS RT=2.47 min andN-[3-([2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]dicarbonimidicdiamide (6 mg). LCMS RT=2.58 min.

xv)N-[3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}ureaacetate

N-[3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]urea(12 mg) in acetic acid (1.5 mL) and water (0.5 mL) was heated at 75° C.for 0.5 h. The solution was then concentrated in vacuo and azeotropedwith MeOH to give the title compound (13 mg). LCMS RT=2.18 min. ES+ve496 (MH)⁺

EXAMPLE 2N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}dicarbonimidicdiamide acetate

Prepared using methods similar to those described in Example 1 xv) LCMSRT=2.30 min. ES+ve 539 (MH)⁺

EXAMPLE 34-((1R)-2-{[2-(4-{2-[(3-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-fluorobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.62 min.

ii)4-((1R)-2-{[2-(4-{2-[(3-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-(2-[(3-fluorobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one(125 mg) in THF (1 mL) was treated with KOSiMe₃ and the resultingsolution was heated at 75° C. for 2 h. The solution was then diluted inMeOH, passed down an SCX-2 cartridge (10 g) and then concentrated invacuo. The residue was purified by chromatography (SPE, 5 g) elutingwith CH₂Cl₂-MeOH-2M NH₃ in MeOH (98:1:1) and then CH₂Cl₂-MeOH-2M NH₃ inMeOH (95:4:1) to give the free base of the title compound. This wasconverted to the acetate salt using acetic acid to give the titlecompound (38 mg). LCMS RT=2.56 min. ES+ve 456 (MH)⁺

EXAMPLE 42-(Hydroxymethyl)-4-((1R)-1-hydroxy-2-{[2-(4-{2-[(3-methylbenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)phenolacetate

i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-methylbenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.69 min.

ii)2-(Hydroxymethyl)-4-((1R)-1-hydroxy-2-{[2-(4-{2-[(3-methylbenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)phenolacetate

Prepared using methods similar to those described in Example 3 ii) LCMSRT=2.62 min. ES+ve 452 (MH)⁺

EXAMPLE 54-((1R)-2-{[2-(4-{2-[(3-Chlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

i)(5R)-3-[2-(4-[2-[(3-Chlorobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.73 min.

ii)4-((1R)-2-{[2-(4-2-[(3-Chlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 3 ii) LCMSRT=2.66 min. ES+ve 472/474 (MH)⁺

EXAMPLE 64-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.90 min.

ii)4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 3 ii) LCMSRT=2.75 min. ES+ve 564 (MH)⁺

EXAMPLE 7N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}acetamideacetate

i)N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)acetamide

A mixture of(5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one{Example 1 xii)} (100 mg), acetic anhydride (21 μL) andN,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at roomtemperature under nitrogen for 20 h. The solution was then diluted inDCM, washed with 2M HCl, NaHCO₃ and brine, dried (MgSO₄) andconcentrated in vacuo to give the title compound (136 mg). LCMS RT=3.24min.

ii)N-[3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]acetamide

Prepared using methods similar to those described in Example 1 xiv) LCMSRT=2.57 min

iii)N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}acetamideacetate

Prepared using methods similar to those described in Example 1 xv) LCMSRT=2.20 min. ES+ve 495 (MH)⁺

EXAMPLE 8N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}nicotinamideacetate

i)N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)nicotinamide

A mixture of(5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one{Example 1 xii)} (100 mg), nicotinoyl chloride hydrochloride (38 mg) andN,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at roomtemperature under nitrogen for 20 h. The solution was then diluted inDCM, washed with 2M HCl, NaHCO₃ and brine, dried (MgSO₄) andconcentrated in vacuo to give the title compound (136 mg). LCMS RT=3.32min.

ii)N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}nicotinamideacetate

Prepared using methods similar to those described in Example 3 ii) LCMSRT=2.34 min. ES+ve 558 (MH)⁺

EXAMPLE 9N-{3-[(2-{4-[2-({(2R)-2-Hydroxyl-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-2-furamideacetate

i)N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)-2-furamide

Prepared using methods similar to those described in Example 8 i) LCMSRT=3.44 min.

ii)N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-2-furamideacetate

N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)-2-furamide(34 mg) in THF (2 mL) was treated with KOSiMe₃ (18 mg) and the resultingsolution was heated at 75° C. for 4 h. The reaction mixture was thenquenched with MeOH and concentrated in vacuo. The residue was thenpurified by HPLC, before dissolving in acetic acid (1 mL) and water(0.33 mL) and heating at 75° for 20 min. The solution was thenconcentrated in vacuo and azeotroped with MeOH to give the titlecompound (3.4 mg). LCMS RT=2.45 min. ES+ve 547 (MH)⁺

EXAMPLE 103-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamideacetate

i)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzonitrile

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.48 min.

ii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzamide

3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzonitrile(125 mg) in THF (3 mL) was treated with KOSiMe₃ (152 mg) and theresulting solution was heated at 75° C. for 4 h. The reaction mixturewas then quenched with MeOH and concentrated in vacuo. The residue wastaken up in EtOAc, washed with phosphate buffer (pH=6.5) and water,dried (MgSO₄) and concentrated in vacuo. The residue was purified bychromatography (SPE, 5 g) eluting with CH₂Cl₂-MeOH-2M NH₃ in MeOH(196:3:1) and then CH₂Cl₂: MeOH: 2M NH₃/MeOH (96:3:1) to give the titlecompound (42 mg). LCMS RT=2.40 min.

iii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamideacetate

Prepared using methods similar to those described in Example 1 xv) LCMSRT=2.12 min. ES+ve 481 (MH)⁺

EXAMPLE 113-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzonitrileacetate

i)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzonitrile

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.48 min.

ii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzonitrile

Prepared using method described in Example 10 ii) but reaction washeated at 75° C. for only 2 h. LCMS RT=2.67 min.

iii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzonitrileacetate

Prepared using methods similar to those described in Example 1 xv) LCMSRT=2.47 min. ES+ve 463 (MH)⁺

EXAMPLE 12N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}methanesulfonamideacetate

i)N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)methanesulfonamide

A solution of(5R)-3-[2-(4-[2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(Example 1 xii)) (117 mg) in pyridine (10 mL) was stirred withmethanesulfonyl chloride (39 mg) at 20° C. for 90 min. The reactionmixture was partitioned between aqueous NaHCO₃ and DCM. The organicsolution was dried (Na₂SO₄), and the solvent was removed in vacuo toyield the title compound (138 mg). LCMS RT=3.30 min

ii)N-[3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]methanesulfonamide

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.59 min

iii)N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}methanesulfonamide acetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.37 min, ES+ve=531 (MH)⁺

EXAMPLE 134-{(1R)-2-[(2-{4-[2-)Benzyloxy]ethoxy]phenyl}ethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

i)(5R)-3-(2-{2-[2-Benzyloxy)ethoxy]phenyl}ethyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

A solution of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(Example 1 viii) (503 mg) in DMF (10 mL) was treated with sodium hydride(60% dispersion in mineral oil) (97 mg) under nitrogen for 20 min. Asolution of 1-[2-(benzyloxy)ethoxy]-4-(2-bromoethyl)benzene (676 mg) inDMF (5 mL) was added and the reaction sfirred for a further 2 h. Thereaction mixture was concentrated in vacuo then the residue was prifiedby chromatography (Biotage, 40 g) eluting with EtOAc-petroleum ether(2:3) to give the title compound (585 mg). LCMS RT=3.66 min

ii)(1R)-2-[(2-{4-[2-(Benzyloxy)ethoxy]phenyl}ethyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Prepared using methods similar to those described in Example 1 (xiv).LCMS RT=2.77 min.

iii)4-{(1R)-2-[(2-{4-[2-(Benzyloxy)ethoxy]phenyl}ethyl)aminol]-1-hydroxyethyl}-2-(hydroxymethyl)acetate

Prepared using methods similar to those described in Example 1 (xv).LCMS RT=2.47 min, ES+ve=438 (MH)⁺

EXAMPLE 14N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-N-phenylureaacetate

i)N-(3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)-N-phenylurea

A stirred mixture of(5R)-3-[2-(4-{2-[(3-Aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(95 mg) in DCM (10 ml) under nitrogen was treated with phenylisocyanate(0.04 ml) and the mixture stirred at 20° C. for 4 h. Isopropanol (10 ml)was added and the mixture stirred for 18 h. The solvents were evaporatedin vacuo to give a residue which was purified by SPE (5 g). Elution withEtOAc-cyclohexane (3:2) gave the title compound (104 mg). LCMS RT=3.53min.

ii)N-[3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]-N-phenylurea

Prepared using methods similar to those described in Example 1 xiv LCMSRT=2.75 min.

iii)N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-N-phenylureaacetate

Prepared using methods similar to those described in Example 1 xv LCMSRT=2.75 min, ES+ve 572 (MH)⁺.

EXAMPLE 154-((1R)-1-Hydroxy-2-{[2-(4-[2-[(3-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

i)2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethylmethanesulfonate

A solution of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one(450 mg) in DCM (20 ml) at 0° C. under nitrogen was treated withdiisopropylethylamine (0.23 ml) followed by methanesulphonyl chloride(0.09 ml) and the mixture was stirred at 0° C. for 1 h. Saturated NaHCO₃solution was added and the mixture was vigorously stirred for 5 min. Thelayers were separated and the organic phase washed with saturated NaHCO₃solution, dried (Na₂SO₄) and the solvent evaporated in vacuo to give thetitle compound (528 mg). LCMS RT=3.15 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-{[2-(trimethylsilyl)ethoxy]methoxy}benzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

A solution of (3-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)methanol inDMF (5 ml) under nitrogen was treated with sodium hydride (18 mg, 60% inoil) and the mixture was stirred at 20° C. for 15 min.2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethylmethanesulfonate (150 mg) was added and the mixture was stirred at 20°C. for 20 h. Phosphate buffer solution (20 ml, pH6.5) was added and themixture was extracted with EtOAc (30 ml). The organic extract was washedwith water (2×20 ml) and dried (Na₂SO₄). The solvent was evaporated invacuo to give a residue which was purified by chromatography on flashsilica gel. Elution with EtOAc-petroleum ether 40°-60° (1:1) gave thetitle compound (90 mg) LCMS RT=4.07 min.

iii)4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 3ii LCMSRT=2.26 min, ES+ve 454 (MH)⁺.

EXAMPLE 164-{(1R)-2-[((1S)-2-{4-[2-(Benzyloxy)ethoxyy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

i) 1-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)acetone

A solution of tert-butyldimethylsilyl chloride (13.6 g) in DMF (50 ml)was added dropwise to stirred solution of 4-hydroxyphenylacetone (12.5g) and imidazole (9.0 g) in DMF (150 ml) at 20° under N₂. After 0.67 hadditional tert-butyldimethylsilyl chloride (4.7 g) was added and thereaction stirred for 0.75 h. The reaction mixture was concentrated invacuo and the residue partitioneed between Et₂O and water. The organicphase was washed with water, brine, dried (MgSO₄) and evaporated todryness. The residue was purified by chromatography on a Biotage (90 g)eluting with cyclohexane-Et₂O (9:1) to give the title compound (17.5 g),ES+ve 282 (M+NH₄)⁺

ii)(1R)-2-{[2-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanolTetramethylammonium (triacetoxy)borohydride (0.94 g) was added to astirred solution of(1R)-2-amino1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.49 g) and1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetone (0.57 g) in CH₂Cl₂(10 ml). Acetic acid (0.2 ml) was added and the reaction stirred for 18h at 20° C. The mixture was diluted with H₂O and extracted with EtOAc.The organic phase was washed with brine, dried (MgSO₄) and evaporated todryness. The residue was purified by chromatography on a Biotage (40 g)eluting with CH₂Cl₂-MeOH-2M NH₃ in MeOH (150:8:1) to give the titlecompound (0.84 g), ES+ve 472 (MH)⁺iii)(5R)-3-[(1R)-2-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-oneand(5R)-3-[(1S)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

1,1′-Carbonyldiimidazole (0.62 g) was added to a solution of(1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(0.83 g) in THF (8 ml). The mixture was stirred for 18 h at 20° C. andpartitioned between Et₂O and water. The organic phase was washed withbrine, dried (MgSO₄) and evaporated to dryness. The residue was purifiedby chromatography on a Biotage (40 g) eluting with cyclohexane-EtOAc(5:1 then 3:1) to give(5R)-3-[(1S)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(0.32 g), LCMS RT=4.17 min and(5R)-3-[(1R)-2-(4-{[tent-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(0.36 g) LCMS RT=4.15 min.

iv)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[(1S)-2-(4-hydroxychenyl)-1-methylethyl]-1,3-oxazolidin-2-one

A solution of tetrabutylammonium fluoride in THF (1M, 0.65 ml) was addedto a stirred solution of(5R)-3-[(1S)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(0.294 g) in THF (3 ml). After stirring at 20° C. for 0.5 h the mixturewas partitioned between EtOAc (30 ml) and H₂O (30 ml). The organic phasewas washed with brine, dried (MgSO₄) and evaporated to dryness. Theresidue was purified by chromatography on a Biotage (40 g) eluting withcyclohexane-EtOAc (3:1) to give the title compound (0.23 g), ES+ve 384(MH)⁺

v)(5R)-3-((1S)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-oneBenzyl 2-bromoethyl ether (0.164 ml) was added to a stirred mixture of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[(1S)-2-(4-hydroxyphenyl)-1-methylethyl]-1,3-oxazolidin-2-one(0.27 g) and cesium carbonate (0.48 g) in DMF (3 ml). The reactionmixture was stirred for 18 h at 20° C. then partitioned between Et₂O (30ml) and water (30 ml). The organic phase was washed with brine, dried(MgSO₄) and evaporated to dryness. The residue was purified bychromatography on a Biotage (8 g) eluting with cyclohexane-Et₂O (1:1) togive the title compound (0.31 g), ES+ve 535 (M+NH₄)⁺vi)(1R)-2-[((1S)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Prepared using method similar to those described in Example 1 xiv ES+ve492 (MH)⁺

vii)4-{(1R)-2-[((1S)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

Prepared using method similar to those described in Example 1 xv LCMSRT=2.52 min ES+ve 452 (MH)⁺

EXAMPLE 174-{(1R)-2-{((1R)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

i)(5R)-3-((1R)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 16 v ES+ve535 (M+NH₄)⁺

ii)(1R)-2-[((1R)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Prepared using methods similar to those described in Example 1 xiv ES+ve492 (MH)⁺

iii)4-{(1R)-2-[((1R)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 1 xv LCMSRT=2.52 min ES+ve 452 (MH)⁺

EXAMPLE 183-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamide

i) 3-Hydroxymethylbenzenesulfonamide

3-(Aminosulfonyl)benzoic acid (2.18 g) was stirred with ice-watercooling and under nitrogen while borane-THF complex (32.5 ml) was addeddropwise over 15 min. After 2 h at 22° further borane-THF complex (16ml) was added. After a further 2 h the mixture was cooled with ice-waterand methanol (40 ml) was added dropwise. After 15 min 2M hydrochloricacid (90 ml) was added and the mixture was left to stand at 21°overnight. The solution was extracted 3 times with ethyl acetate and theorganic layers were combined and washed twice with brine, dried (MgSO₄)and concentrated. This solution was loaded onto a column of silica gel(200 g) and the column was run with ethyl acetate and then 10% methanolin ethyl acetate to give the title compound (1.595 g), LCMS RT=0.83 min.

ii)3-(Hydroxymethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Sodium hydride (60% oil dispersion, 0.315 g) was added to3-hydroxymethylbenzenesulfonamide (0.67 g) with stirring in DMF (20 ml)under nitrogen at 20°. After 15 min, 2-(trimethylsilyl)ethoxymethylchloride (1.27 ml) was added and stirring was continued for 1.5 h. pH6.4 Phosphate buffer and ethyl acetate were added. The aqueous layer wasextracted twice with ethyl acetate and the combined organic layers werewashed twice with brine, dried (MgSO₄) and evaporated to an oil. Thisoil in dichloromethane was loaded onto a column of silica gel (75 g) setup in 10% ethyl acetate in 40-60 petroleum ether. The column was runwith this, then 20%, 30% and 50% ethyl acetate in 40-60 petroleum etherto give the title compound (0.74 g) LCMS RT=4.00 min.

iii)3-(Bromomethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

3-(Hydroxymethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide(0.735 g) was stirred with ice-water cooling in dichloromethane (32 ml)under nitrogen and carbon tetrabromide (0.962 g) and triphenylphosphine(0.646 g) were added successively. After 5 min the cooling bath wasremoved and the mixture was stirred at 21° for 4 h. The mixture waspoured onto an SPE silica cartridge (10 g). The cartridge was elutedwith dichloromethane to give the title compound (0.21 g) LCMS RT=4.31min.

iv)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those in Example 1 xi) LCMS RT=4.38min

v)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-NN-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those in Example 1 xiv) LCMS RT=3.50min

vi)3-1(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamide

3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide(0.015 g) was heated at 75° for 6 h in acetic acid (1.5 ml) and water(0.75 ml). The solution was evaporated to dryness and re-evaporatedtwice with methanol to give crude product (0.012 g). This was purifiedby preparative layer chromatography on a silica plate (20×20 cm) whichwas developed twice in dichloromethane:ethanol: 0.880 ammonia solution,25:8:1. After elution of the required band using methanol indichloromethane, the eluate was evaporated to dryness and re-evaporatedsuccessively with acetic acid in methanol and then methanol to give thetitle compound (0.0037 g) LCMS RT=2.19 min. ES+ve 517 (MH)⁺

EXAMPLE 193-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzenesulfonamide

i) 3-(Hydroxymethyl)-N-isopropylbenzenesulfonamide

Sodium hydride (60% oil dispersion, 0.177 g) was added to3-hydroxymethylbenzenesulfonamide (0.77 g) with stirring in DMF (15 ml)under nitrogen at 21°. After 10 min, isopropyl iodide (0.45 ml) wasadded followed by a further 0.3 ml after 1 h. After an additional 2 hmore isopropyl iodide (0.2 ml) was added. After 3 days more sodiumhydride oil dispersion (0.08 g) was added. After another day, thesolution was poured into water acidified with 2M hydrochloric acid andthe product was extracted with ethyl acetate twice. The combinedextracts were washed with brine and evaporated to an oil. This oil wasloaded onto a column of silica gel (60 g) and the column was elutedsuccessively with 30%, 50% and 70% ethyl acetate in 40-60 petroleumether to give the title compound (0.527 g) LCMS RT=2.22 min.

ii)3-(Hydroxymethyl)-N-isopropyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those in example 18 ii) LCMS RT=3.75min

iii)3-(Bromomethyl)-N-isopropyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those in example 18 iii) LCMS RT=3.91min

iv)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-isopropyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those in Example 1 xi) LCMS RT=4.07min

v)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-isopropyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those in Example 1 xiv) LCMS RT=3.26min

vi)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzenesulfonamide

Prepared using methods similar to those in Example 1 xv) LCMS RT=2.44min. ES+ve 559 (MH)⁺

EXAMPLE 203-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzoicacid acetate

i) Methyl3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzoate

Prepared using methods similar to those described in Example 1 xi) LCMSRT=3.66 min.

ii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzoicacid

Prepared using methods similar to those described in Example 1 xiv) LCMSRT=2.70 min.

iii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzoicacid acetate

Prepared using methods similar to those described in Example 1 xv) LCMSRT=2.32 min. ES+ve 482 (MH)⁺

EXAMPLE 214-((1R)-2-{[2-(4-{2-[(4-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(4-fluorobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi). LCMSRT=3.70 min.

ii)4-((1R)-2-{[2-(4-{2-[(4-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 3 ii). LCMSRT=2.49 min. ES+ve 456 (MH)⁺

EXAMPLE 224-((1R)-2-{[2-(4-[2-[(2,6-Dichlorobenzyl)oxy]ethoxy]phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

i)(5R)-3-[2-(4-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi). LCMSRT=3.79 min.

ii)4-((1R)-2-{[2-(4-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate(5R)-3-[2-(4-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(160 mg) in THF (4 ml) was treated with KOSiMe₃ (179 mg) and theresulting solution was heated at 75° C. for 2 h. The reaction mixturewas then quenched with MeOH and concentrated in vacuo. The residue wasthen diluted in MeOH, and purified on an SCX-2 cartridge (10 g) elutingwith EtOH followed by 10% aqueous NH₃ in EtOH. The ammonia fractionswere then combined and concentrated in vacuo. The residue was dissolvedin acetic acid (3 ml) and water (1 ml) and heated at 75° C. for 20 min.The solution was then concentrated in vacuo and azeotroped with MeOH togive the title compound (115 mg). LCMS RT=2.49 min, ES+ve 506 (MH)⁺

EXAMPLE 23N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamideformate andN-(tert-butoxycarbonyl)-N-{3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamideformate

i)N-(tert-Butoxycarbonyl)-N-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)sulfamide

A solution of chlorosulfonylisocyanate (34 mg) in DCM (1 ml) was cooledin ice before adding tert-butanol (0.023 ml). The mixture was thenstirred for 2 h when diisopropylethylamine (0.13 ml) and a solution of(5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy{phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one{Example 1 xii)} (138 mg) in DCM (3 ml) was added. The resultingsolution was then allowed to warm to room temperature and stoodovernight. The solution was then diluted in DCM, washed with phosphatebuffer (pH=6.5) and water, dried (MgSO₄) and concentrated in vacuo. Theresidue was then purified by chromatography (SPE, 5 g) eluting withcyclohexane-EtOAc (1:1) and then EtOAc to give the title compound (74mg). LCMS RT=3.57 min.

ii) N-(tert-Butoxycarbonyl)-N-[3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]sulfamide

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.79 min.

iii)N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamideformate andN-(tert-butoxycarbonyl)-N-{3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamideformate

N-(tert-Butoxycarbonyl)-N-[3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]sulfamide(15 mg) in acetic acid (1.5 ml) and water (0.5 ml) was heated at 75° C.for 0.5 h. The solution was then concentrated in vacuo and azeotropedwith MeOH. The residue was purified by HPLC to give the title compoundsN-{3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamideformate (1.5 mg) LCMS RT=2.21 min, ES+ve 532 (MH)⁺andN-(tert-butoxycarbonyl)-N-{3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamideformate (0.9 mg). LCMS RT=2.51 min ES+ve 630 (MH)⁺

EXAMPLE 244-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxamethyl)phenolacetate

i)(5R-3-{2-[4-(2-{[3-Cyclopentylthio)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

To a solution of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one{Example6 i)} (400 mg) in N-methylpyrrolidinone (3 ml) and Et₃N (0.5 ml) wasadded diphenylphosphinoferrocene (dppf) (84 mg) andtris(dibenzylideneacetone)dipalladium (0) [Pd₂(dba)₃] (34 mg). Thesolution was then flushed with nitrogen for 15 min before addingcyclopentylmercaptan (136 mg) and heating at 60° C. for 4 h. Thesolution was then allowed to cool to room temperature before pouringinto aq. NaHCO₃ solution and extracting with EtOAc. The combined organiclayers were then washed with water, dried (MgSO₄) and concentrated invacuo. The residue was purified by chromatography (Biotage, 40 g)eluting with CH₂Cl₂-MeOH (500:1) to give the title compound (276 mg).LCMS RT=4.08 min.

ii)(5R)-3-{2-[4-(2-{[3-(Cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

A solution of(5R)-3-{2-[4-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(276 mg) in EtOH (15 ml) and water (5 ml) was treated with sodiumperiodate (391 mg) and stirred at room temperature under nitrogen for 3h. The solution was concentrated in vacuo before pouring into water andextracting with EtOAc. The combined organic layers were washed withwater, dried (MgSO₄) and concentrated in vacuo to give the titlecompound (278 mg). LCMS RT=3.42 min.

iii)(5R)-3-{2-[4-(2-{[3-(Cyclopentylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-1,3-oxazolidin-2-one

A solution of(5R)-3-{2-[4-(2-{[3-(cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(56 mg) in CH₂Cl₂ (2 ml) was cooled in an ice bath under a nitrogenatmosphere. To this was added 3-chloroperoxybenzoic acid (30 mg) and theresulting solution was allowed to warm to room temperature and stirredfor 2 h. The solution was then washed with sodium sulphite, to removeany excess peroxide, and water. The combined organic layers were thendried (MgSO₄) and concentrated in vacuo to give the title compound (70mg). LCMS RT=3.70 min.

iv)(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.91 min.

v)4-[(1R)-2-({2-[4-(2-{[3-(Cylopentylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.62 min ES+ve 570 (MH)⁺

EXAMPLE 254-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsufinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenolacetate

i)(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Prepared using methods similar to those described in Example 1 xiv)using(5R)-3-{2-[4-(2-{[3-(cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one{Example 24 ii)}. LCMS RT=2.73 min.

ii)4-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.37 min.

EXAMPLE 264-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-isopropoxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

i) (4-Isopropoxyphenyl)methanol

4-Hydroxybenzylalcohol (1 g) in DMF (10 ml) under nitrogen at 0° C. wastreated portionwise with sodium hydride (355 mg). The resulting solutionwas stirred for 0.5 h before isopropyl bromide (0.99 g) was added, andthe solution was stirred for a further 18 h. Phosphate buffer (pH=6.5)was then added and the solution was extracted with EtOAc. The combinedorganic layers were then washed with water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography(Biotage, 90 g) eluting with 40-60° C. petroleum ether-EtOAc (4:1) togive the title compound (931 mg). LCMS RT=2.51 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(4-isopropoxybenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

A solution of (4-isopropoxyphenyl)methanol (93 mg) in DMF (2 ml) wastreated with sodium hydride (27 mg) under nitrogen and stirred for 0.5h. To this was added the2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethylmethanesulfonate (357 mg) {Example 15 i)} and the resulting solution wasstirred for 18 h under nitrogen. The solution was then diluted in EtOAc,washed with water, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by chromatography (Biotage, 40 g) eluting with 40-60° C.petroleum ether-EtOAc (2:1) to give the title compound (156 mg). LCMSRT=3.76 min.

iii)4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-isopropoxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 22 ii).LCMS RT=2.56 min ES+ve 496 (MH)⁺

EXAMPLE 27 4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

i) (4-{[2-(Trimethylsilyl)ethoxy]methoxy}phenyl)methanol

Prepared using methods similar to those described in Example 26 i). LCMSRT=3.42 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-[2-[(4-{[2-(trimethylsilyl)ethoxy]methoxy}benzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 26 ii).LCMS RT=4.09 min.

iii)4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenolacetate

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(4-{[2-(trimethylsilyl)ethoxy]methoxy}benzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one(287 mg) in THF (5 ml) was treated with KOSiMe₃ (570 mg) and theresulting solution was heated at 75° C. for 3 h. The reaction was thenquenched in MeOH and concentrated in vacuo. The residue was purified bychromatography (SCX-2, two 10 g cartridges) eluting with 10% MeOH-CH₂Cl₂and then 10% 2M NH₃ in MeOH—CH₂Cl₂. The residue was then dissolved inAcOH (3 ml) and water (1 ml) and heated at 75° C. for 2 h. The solutionwas then concentrated in vacuo and azeotroped with MeOH. The residue waspurified by HPLC to give the formate salt of the title compound. Thiswas converted to the acetate salt by dissolving in acetic acid andevaporating under reduced pressure to give the title compound (14 mg).LCMS RT=2.34 min ES+ve 454 (MH)⁺

EXAMPLE 283-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxymethyl]-N-isopropylbenzamideacetate

i) 2-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)ethanol

Sodium hydride (60% dispersion in mineral oil, 145 mg) was addedportionwise to a solution of 4-(2-hydroxyethyl)phenol (502 mg) in THF(15 ml) and the mixture was stirred at 20° C. for 30 min.tert-Butyldimethylsilyl chloride (547 mg) was added and the mixture wasstirred for 75 min. Phosphate buffer solution (pH 6.5) was added and themixture was extracted with EtOAc. The combined extracts were dried(Na₂SO₄) and the solvent evaporated in vacuo to give a residue which waspurified by SPE (10 g). Elution with DCM-cyclohexane (1:3) then DCM thenEtOAc gave the title compound (658 mg). LCMS RT=3.62 min.

ii) 2-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)ethyl methanesulfonate

A solution of 2-(4-((tert-butyl(dimethyl)silyl]oxy}phenyl)ethanol (653mg) and diisopropylethylamine (1.8 ml) in DCM (15 ml) at 0° undernitrogen was treated with methanesulfonyl chloride (0.44 ml) and themixture was stirred at 0° C. for 6 h. Saturated NaHCO₃ solution wasadded and the mixture stirred for 15 min. Water (20 ml) was added andthe mixture was extracted with DCM. The extract was dried (Na₂SO₄) andthe solvent evaporated in vacuo to give the title compound (904 mg).LCMS RT=3.85 min.

iii) [4-(2-Bromoethyl)phenoxy](tert-butyl)dimethylsilane

A solution of 2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethylmethanesulfonate (1.064 g) in acetonitrile (35 ml) was treated withtetrabutylammonium bromide (2.346 g) at 50° C. for 2.5 h. The mixturewas cooled to 20° C. and the solvent was evaporated in vacuo. Theresidue was dissolved in EtOAc and the resulting solution washed withwater and dried (Na₂SO₄). Solvent evaporation in vacuo gave the titlecompound (991 mg). LCMS RT=4.22 min.

iv)(1R)-2-{[2-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

A solution of [4-(2-bromoethyl)phenoxy](tert-butyl)dimethylsilane (479mg) in DMF (20 ml) under nitrogen was treated with(1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (678 mg)and the mixture was stirred at 20° C. for 9.5 h. Phosphate buffersolution (pH 6.5) was added and the mixture was extracted with EtOAc.The extract was washed with water and dried (Na₂SO₄). Solventevaporation in vacuo gave a residue which was purified by SPE (10 g).Elution with DCM then DCM-EtOH-0.880 ammonia solution (300:8:1) then(150:8:1) gave the title compound (991 mg). LCMS RT=3.13 min.

v)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-hydroxyphenyl)ethyl]-1,3-oxazolidin-2-one

A solution of(1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(4.803 g) in THF (100 ml) under nitrogen was treated with1,1′carbonyldimidazole (1.702 g) and the mixture was stirred at 20° for21.5 h. Water (125 ml) was added, the mixture was stirred for 10 min andthen extracted with Et₂O. The extract was dried (Na₂SO₄) and the solventevaporated in vacuo. The residue was dissolved in THF (60 ml) and wastreated with a solution of tetrabutyl ammonium fluoride in THF (1.0 M,15.95 ml). The mixture was stirred at 20° for 100 min, water (30 ml) wasadded and the mixture was extracted with Et₂O. The extract was washedwith water, dried (Na₂SO₄) and the solvent evaporated in vacuo to give aresidue which was purified by chromatography on a Biotage cartridge (90g). Elution with EtOAc-petroleum ether (2:3) gave the title compound(2.82 g). LCMS RT=3.01 min ES+ve 370 (MH)⁺.

vi) 3-[(2-Hydroxyethoxy)methyl]benzonitrile

A solution of ethylene glycol (7.5 g) in DMF (50 ml) under nitrogen at0° C. was treated portionwise with sodium hydride (1.35 g) and stirredfor 0.5 h. 3-Cyanobenzylbromide (4.74 g) was then added and the solutionwas allowed to warm to room temperature and stirred for 4 h. Thesolution was then concentrated in vacuo to remove the DMF. The residuewas taken up in EtOAc, washed with phosphate buffer (pH=6.5) and water,dried (MgSO₄) and concentrated in vacuo. The residue was then purifiedby chromatography (Biotage, 2×90 g) eluting with 40-60° C. petroleumether-EtOAc (1:1) to give the title compound (2.62 g). LCMS RT=2.07 min.

vii) Methyl 3-[(2-hydroxyethoxy)methyl]benzoate

A solution of 3-[(2-hydroxyethoxy)methyl]benzonitrile (1 g) in MeOH (20ml) was treated with conc. H₂SO₄ (10 ml) at 0° C. The solution was thenallowed to warm to room temperature before heating at reflux for 10 h.Aqueous sodium carbonate was added to neutralise the cooled solutionbefore extracting with EtOAc. The combined organic layers were thenwashed with water, dried (MgSO₄) and concentrated in vacuo. The residuewas then purified by chromatography (Biotage, 90 g) eluting with40°C.-60° C. petroleum ether-EtOAc (3:2) to give the title compound (650mg). LCMS RT=2.33 min.

viii) Methyl3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzoate

(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-hydroxyphenyl)ethyl]-1,3-oxazolidin-2-one{Example28 v)} (300 mg), methyl 3-[(2-hydroxyethoxy)methyl]benzoate (340 mg) andtriphenylphosphine (642 mg) were dissolved in DCM (10 ml) and stirredfor 15 min. To this was added 1,1′-(azodicarbonyl)dipiperidine (612 mg)and the solution was stirred for 16 h. The solution was then diluted inDCM, washed with water, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by chromatography (Biotage, 90 g) eluting withCH₂Cl₂-MeOH (250:1) to give the title compound (450 mg). LCMS RT=3.62min.

ix)3-{[2-(4-}2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzoicacid

Prepared using methods similar to those described in Example 1 x). LCMSRT=3.45 min.

x)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-isopropylbenzamide

A solution of3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzoicacid (90 mg) and isopropyl amine (9.7 mg) in DMF (2 ml) was cooled to 0°C. and treated with diisopropylethylamine (0.057 ml) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (62 mg). This was then stirred for 8 h before diluting in EtOAcand washing sequentially with 2M HCl, NaHCO₃ (aq) and brine. Thecombined organic layers were then dried (MgSO₄) and concentrated invacuo to give the title compound(112 mg). LCMS RT=3.36 min.

xi)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-isopropylbenzamide

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.60 min.

xii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzamideacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.34 min ES+ve 523 (MH)⁺

EXAMPLE 29N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamideacetate

i)N-Cylohexyl-3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzamide

Prepared using methods similar to those described in Example 28 x). LCMSRT=3.65 min.

ii)N-Cyclohexyl-3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzamide

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.78 min.

iii)N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamideacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.57 min ES+ve 563 (MH)⁺

EXAMPLE 30N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamideacetate

i) 3-[(Cyclohexylamino)sulfonyl]benzoic acid

A mixture of 3-(chlorosulfonyl)benzoic acid (2.00 g) and DCM (20 ml)under nitrogen at 0° was treated with cyclohexylamine (3.63 ml) and themixture was stirred at 0° C. for 0.5 h. The solvent was evaporated invacuo and the residue was treated with 1M potassium hydrogen sulfatesolution (50 ml) and extracted with EtOAc. The combined extracts weredried (Na₂SO₄) and the solvent evaporated in vacuo to give the titlecompound (2.28 g). LCMS RT=3.16 min.

ii) N-Cyclohexyl-3-(hydroxymethyl)benzenesulfonamide

A solution of 3-[(cyclohexylamino)sulfonyl]benzoic acid (2.25 g) in THF(100 ml) under nitrogen at 0° was treated dropwise with 1M borane-THFsolution (23.82 ml). The mixture was stirred at 0° C. for 0.5 h and thenat 20° C. for 72 h. The mixture was cooled to 0° C. and MeOH (20 ml) wasadded dropwise. The mixture was stirred for 15 min and then 2Nhydrochloric acid (50 ml) was added and the mixture was allowed to warmto 20° C. The bulk of the organic solvents were removed by evaporationin vacuo and the residual aqueous phase was extracted with EtOAc (2×40ml). The combined extracts were dried (Na₂SO₄) and the solventevaporated in vacuo. The residue was purified by SPE on alumina (10 g,activated, neutral, Brockmann 1). Elution with MeOH-dichloromethane(1:20) gave the title compound (1.944 g). LCMS RT 2.95 min.

iii)N-Cyclohexyl-3-(hydroxymethyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

A solution of N-cyclohexyl-3-(hydroxymethyl)benzenesulfonamide (1.744 g)in DMF (30 ml) under nitrogen was treated with sodium hydride (60%dispersion in mineral oil, 311 mg) and the mixture stirred at 20° C. for0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.15 ml) was added andthe mixture was stirred for a further 2 h at 20° C. Phosphate buffersolution (pH 6.5, 50 ml) and water (50 ml) were added and the mixturewas extracted with EtOAc. The combined extracts were washed with waterand dried (Na₂SO₄). Solvent evaporation in vacuo gave a residue whichwas purified by flash chromatography on silica gel. Elution withEtOAc-petroleum ether (3:7) gave the title compound (1.917 g). LCMSRT=3.83 min.

iv)N-Cyclohexyl-3-{[2-(4-[2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

A solution ofN-cyclohexyl-3-(hydroxymethyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide(207 mg) in DMF (5 ml) under nitrogen was treated with sodium hydride(60% dispersion in mineral oil, 24 mg) and the mixture stirred at 20° C.for 15 min. A solution of2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethylmethanesulfonate [Example 15 i)] (170 mg) in DMF (3 ml) was added andthe mixture stirred at 20° C. for 18 h. Phosphate buffer solution (pH6.5, 15 ml) and water (15 ml) were added and the mixture was extractedwith EtOAc. The combined extracts were washed with water and dried(Na₂SO₄). Solvent evaporation in vacuo gave a residue which was purifiedby “Flashmaster” chromatography on silica gel. Elution withEtOAc-cyclohexane (2:3) gave the title compound (125 mg). LCMS RT=4.35min.

v)N-Cyclohexyl-3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those described in Example 1 xiv. LCMSRT=3.52 min.

vi)N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamideacetate

Prepared using methods similar to those described in Example 1 xv. LCMSRT=2.66 min; ES+ve 599 (MH)⁺.

EXAMPLE 313-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-methylbenzenesulfonamide acetate

i) 3-[(Methylamino)sulfonyl]benzoic acid

Prepared using methods similar to those described in Example 30 i). LCMSRT=2.14 min.

ii) 3-(Hydroxymethyl)-N-methylbenzenesulfonamide

Prepared using methods similar to those described in Example 30 ii).LCMS RT=1.86 min.

iii)3-(Hydroxymethyl)-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those described in Example 30 iii)LCMS RT=3.50 min.

iv)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those described in Example 30 iv).LCMS RT=3.98 min.

v)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide

Prepared using methods similar to those described in Example 1 xiv. LCMSRT=3.21 min.

vi)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-methylbenzenesulfonamideacetate

Prepared using methods similar to those described in Example 1 xv. LCMSRT=2.29 min, ES+ve 531 (MH)⁺.

EXAMPLE 324-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenolacetate

i) [3-(Isopropylthio)phenyl]methanol

3-Iodobenzylalcohol (1.40 g) was stirred withtris(dibenzylideneacetone)dipalladium (0.08 g) and1,1′-bis(diphenylphosphino)ferrocene (0.09 g) in N-methylpyrrolidone (20ml) and triethylamine (10 ml) at 21° for 10 min while sparging withnitrogen. i-Propyl mercaptan (0.83 ml) was added and the mixture washeated to 60° C. for 2 h. The mixture was partitioned between diethylether and water and the aqueous layer was extracted with more diethylether. The combined organic layers were washed with brine, dried (MgSO₄)and the volatiles were distilled off on a steam bath. The residue waschromatographed on silica gel (50 g) in diethyl ether-petroleum ether(40-60° C.)(1:9, and then 1:4) to give the title compound (0.973 g).LCMS RT=2.93 min.

ii) 1-(Bromomethyl)-3-(isopropylthio)benzene[3-(Isopropylthio)phenyl]methanol (0.365 g) was stirred with phosphorustribromide (0.19 ml) in dichloromethane (10 ml) at 21° C. for 2 h. Thesolution was washed with water plus sodium bicarbonate and the aqueouslayer was back extracted with dichloromethane. The combined organiclayers were washed with water, dried (MgSO₄) and evaporated to give thetitle compound (0.226 g). LCMS RT=3.64 min.iii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-[4-(2-{[3-(isopropylthio)benzyl]oxy}ethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 1 xi). LCMSRT=3.89 min.

iv)(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 24 ii).LCMS RT=3.29 min.

v)(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethanol(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one(0.07 g) was stirred with potassium trimethylsilanolate (0.14 g) in THF(5 ml) under reflux for 2.5 h. After cooling the mixture was dilutedwith dichloromethane and poured onto a 10 g Bond Elut silica cartridgewhich was eluted successively with dichloromethane, thendichloromethane:ethanol:0.880 ammonia solution (100:8:1 and then 50:8:1)to give the title compound (0.031 g). LCMS RT=2.61 min.vi)4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.26 min ES+ve 528 (MH)⁺

EXAMPLE 334-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenolacetate

i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-{[3-(isopropylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 24 iii).LCMS RT=3.43 min

ii)(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-({2-[4-(2-{[3-(isopropylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethanol

Prepared using methods similar to those described in Example 32 v). LCMSRT=2.63 min

iii)4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.33 min ES+ve 545 (MH)⁺

EXAMPLE 342-(Hydroxymethyl)-4-[(1R)-1-hydroxy-2-({2-[4-(4-phenylbutoxy)phenyl]ethyl}amino)ethyl]phenolacetate

i) 1-(2-Bromoethyl)-4-(4-phenylbutoxy)benzene

A solution of 2-[4-(4-phenylbutoxy)phenyl]ethanol (120 mg) and carbontetrabromide (250 mg) in DCM (7 ml) under nitrogen was treated withtriphenylphosphine (175 mg), the mixture was stirred at 20° for 18 h andthe mixture was then applied to an SPE cartridge (5 g). Elution with DCMgave an oil which was further purified by flash chromatography on silicagel. Elution with Et₂O-petroleum ether (1:20) gave the title compound(1.917 g). LCMS RT=4.06 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(4-phenylbutoxy)phenyl]ethyl}-1,3-oxazolidin-2-one

A solution of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (82mg) in DMF under nitrogen was treated with sodium hydride (60%dispersion in mineral oil, 16 mg) and the mixture stirred at 20□ for 10min. A solution of 1-(2-bromoethyl)-4-(4-phenylbutoxy)benzene (110 mg)in DMF (1 ml) was added and the mixture was stirred at 20° C. for 2 h.Phosphate buffer solution (pH 6.5, 10 ml) and water (20 ml) were addedand the mixture was extracted with EtOAc. The combined extracts werewashed with water and dried (Na₂SO₄). Solvent evaporation in vacuo gavea residue which was partially purified by SPE (5 g). Elution with DCMthen EtOAC-cyclohexane (1:1) gave material which was further purified byflash chromatography on silica gel. Elution with EtOAc-petroleum ether(3:2) gave the title compound (75 g). LCMS RT=3.92 min.

iii)(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-({2-[4-(4-phenylbutoxy)phenyl]ethyl}amino)ethanol

Prepared using methods similar to those described in Example 1 xiv. LCMSRT=2.99 min.

iv)2-(Hydroxymethyl)-4-[(1R)-1-hydroxy-2-({2-[4-(4-phenylbutoxy)phenyl]ethyl}amino)ethyl]phenolacetate

Prepared using methods similar to those described in Example 1xv. LCMSRT-=2.84 min. ES+ve 436 (MH)⁺.

EXAMPLE 354-{(1R)-1-Hydroxy-2-[(2-{4-[4-(3-hydroxyphenyl)butoxy]phenyl}ethyl)amino]ethyl}-2-(hydroxymethyl)phenolacetate

i) 3-(4-Hydroxybut-1-ynyl)phenyl acetate

A solution of 3-iodophenyl acetate (5.6 g) (J. Org. Chem. 1983,48,1542-4) in acetonitrile (100 mL) was treated with (Ph₃P)₂PdCl₂ (673mg) and Cul (368 mg) and stirred at room temperature. 3-Butyn-1-ol (1.78g) was added and the reaction mixture stirred for a further 20 h andconcentrated in vacuo. The residue was purified by chromatography (SPE,gradient from cyclohexane to DCM) to give the title compound. LCMSRT=2.54 min

ii) 3-(4-Hydroxybutyl)phenyl acetate

A solution of 3-(4-hydroxybut-1-ynyl)phenyl acetate (4.47 g) washydrogenated over 5% Pd on carbon in ethyl acetate (100 mL) and ethanol(100 mL) over 20 h. The reaction mixture was filtered through celiteunder nitrogen, and the filtrate was concentrated in vacua. The residuewas purified by chromatography (SPE, gradient from cyclohexane to EtOAc)to give the title compound. LCMS RT=2.64 min

iii) 3-(4-Bromobutyl)phenyl acetate

A solution of 3-(4-hydroxybutyl)phenyl acetate (416 mg) in DCM (10 mL)was treated with carbon tetrabromide (1.16 g) and triphenylphosphine(791 mg) and stirred at room temperature for 15 min prior toconcentration in vacuo. The residue was purified by chromatography (SPE,DCM-petrol 1:1) to give the title compound. LCMS RT=3.58 min

iv)3-[4-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)butyl]phenylacetate

A solution of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-hydroxyphenyl)ethyl]-1,3-oxazolidin-2-one(Example 28 v) (37 mg) in dry DMF (0.4 mL) was treated with caesiumcarbonate (65 mg) and 3-(4bromobutyl)phenyl acetate (0.2 mmol) as asolution in DMF (0.5 mL). Further DMF was added (1 mL) and the reactionmixture stirred at 50° C. for 24 h. The reaction mixture was cooled toroom temperature and concentrated in vacuo in a genevac. The residue wassuspended in chloroform and filtered to remove inorganic salts. Thefiltrate was added to the top of a pre-conditioned NH₂ propyl cartridge(1 g). The cartridge was washed with chloroform and methanol and thetitle compound eluted with 2M NH₃-MeOH. LCMS RT=3.86 min

v)4-{(1R)-1-Hydroxy-2-[(2-{4-]4-(3-hydroxyphenyl)butoxy]phenyl}amino]ethyl}-2-(hydroxymethyl)phenolacetate

Prepared using methods similar to those described in Example 3 ii). LCMSRT=3.81 min; ES+ve m/z451 (MH)⁺

EXAMPLE 364-((1R)-2-{[2-(4-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

i) [4-(3-Bromophenyl)butoxy](tert-butyl)diphenylsilane

A solution of 4-(3-bromophenyl)butan-1-ol (5 g) (WO 0266422 A1) in dryDMF was treated with imidazole (1.8 g) and tert-butyldiphenylsilylchloride (7.2 g) and stirred at room temperature for 16 h. The reactionmixture was partitioned between water and EtOAc. The organic phase waswashed with 2M HCl, water, sat. NH₄Cl(aq), water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography (SPE,Gradient between cyclohexane and cyclohexane-EtOAc (5:1) to give thetitle compound. LCMS RT=4.82 min

ii) tert-Butyl{4-[3-(cyclopentylthio)phenyl]butoxy}diphenylsilane

Prepared using methods similar to those described for Example 24 i).LCMS RT=4.94 min.

iii) tert-Butyl{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}diphenylsilane

Prepared by methods similar to those described for Example 24 ii. LCMSRT=4.45 min.

iv) 4-[3-(Cyclopentylsulfinyl)phenyl]butan-1-ol

A solution oftert-butyl{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}diphenylsilane (690mg) in dry THF (10 ml) was treated with a solution oftetra-n-butylammonium fluoride in THF (1M; 3 ml) and the resultantreaction mixture stirred at room temperature for 5 h prior toconcentration in vacuo. The residue was purified by chromatography (SPE,Gradient between cyclohexane and EtOAc) to give the title compound. LCMSRT=2.64 min.

v) 1-(4-Bromobutyl)-3-(cyclopentylsulfinyl)benzene

Prepared by methods similar to those described for Example 35 iii). LCMSRT=3.48 min.

vi)(5R)-3-[2-(4-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}phenyl)ethyl]-5-(2.2dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Prepared by methods similar to those described for Example 35 iv). LCMSRT=3.81 min.

vii)4-((1R)-2-{[2-(4-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenolacetate

Prepared by methods similar to those described for Example 3 ii). LCMSRT=2.74 min. ES+ve m/z 552 (MH)⁺

EXAMPLE 374-{(1R)-2-[(2-{4-[4-(2,6-Dichlorophenyl)butoxy]phenyl]ethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

i) 4-(2,6-Dichlorophenyl)but-3-yn-1-ol

Prepared by methods similar to those described for Example 35 i). LCMSRT=3.06 min.

ii) 4-(2,6-Dichlorophenyl)butan-1-ol

Prepared by methods similar to those described for Example 35 ii) LCMSRT=3.22 min.

iii) 2-(4-Bromobutyl)-1,3-dichlorobenzene

Prepared by methods similar to those described for Example 35 iii) LCMSRT=4.17 min.

iv)(5R)-3-(2-{4-[4-(2,6-Dichlorophenyl)butoxy]phenyl}ethyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Prepared by methods similar to those described for Example 35 iv) LCMSRT=4.26 min.

v)4-{(1R)-2-[(2-{4-[4-(2,6-Dichlorophenyl)butoxy]phenyl}ethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenolacetate

Prepared by methods similar to those described for Example 3 ii). LCMSRT=3.00 min. ES+ve m/z 504 (MH)⁺

EXAMPLE 383-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzenesulfonamideacetate

i) 3-(4-Hydroxybut-1-ynyl)benzenesulfonamide

Prepared by methods similar to those described for Example 35 i) LCMSRT=2.17 min.

ii) 3-(4-Hydroxybutyl)benzenesulfonamide

Prepared by methods similar to those described for Example 35 ii) LCMSRT=2.14 min.

iii) 4-[3-(Aminosulfonyl)phenyl]butyl methanesulfonate

A solution of 3-(4-hydroxybutyl)benzenesulfonamide (458 mg) in dry THF(10 ml) was treated with triethylamine (0.307 ml) and the resultantsolution cooled to 0° C. Methanesulfonyl chloride (0.17 ml) was addeddropwise. The mixture was allowed to warm to room temperature andstirred for a further 15 minutes. The reaction mixture was partitionedbetween 1M HCl_(aq) and EtOAc. The aqueous phase was washed with EtOAc.The combined organic phase was dried (MgSO₄) and concentrated in vacuoto give the title compound LCMS RT=2.67 min.

iv)3-[4-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl]phenoxy)butyl]benzenesulfonamide

Prepared by methods similar to those described for Example 35 iv) LCMSRT=3.56 min.

v)3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzenesulfonamideacetate

Prepared by methods similar to those described for Example 1 xv) LCMSRT=2.21 min. ES+ve m/z 515 (MH)⁺

EXAMPLE 39N-[3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)phenyl]ureaacetate

i) 3-(4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)aniline

A solution of the 4-(3-aminophenyl)butan-1-ol [Hua Hsueh Hsueh Pao 1964,30, 166-75. CAN 61:47615] (3.66 g) in dry DMF (30 ml) was treated withimidazole (1.66 g) and tert-butyldimethylsilyl chloride (3.5 g). Thereaction mixture was stirred at room temperature for 18 h. The reactionmixture was concentrated in vacuo and the residue partitioned betweensat. NH₄Cl_((aq)) and ethyl acetate. The aqueous phase was extractedwith EtOAc and the combined organic phase washed with water, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bychromatography (Biotage, Petroleum ether-EtOAc 9:1) to give the titlecompound. LCMS RT=3.89 min.

ii) N-[3-(4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)phenyl]urea

A solution of 3-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)aniline (5.16g) in dry DCM (50 ml) was treated dropwise with a solution oftrichloroacetyl isocyanate (2.36 ml) in dry DCM (6 ml) over 10 min. Thereaction mixture was stirred at room temperature for 10 min prior toaddition of 2M NaOH (50 ml). The reaction mixture was stirred at 70° C.for 5 h and room temperature for 16 h. The aqueous phase was extractedwith DCM and the combined organic layers washed with water andconcentrated in vacuo. The residue was purified by chromatography(biotage, EtOAc-Petrol 2:1) to give the title compound. LCMS RT=3.78min.

iii) N-[3-(4-hydroxybutyl)phenyl]urea

A solution of N-[3-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)phenyl]urea(5.67 g) in THF (50 ml) was treated with TFA (13.56 ml) and stirred atroom temperature for 1 h. Further TFA (5 ml) was added and the reactionmixture stirred for a further 16 hours. The reaction mixture wasconcentrated in vacuo. The residue was co-evaporated with methanol andthen suspended in methanol and heated at reflux for 20 h prior toconcentration in vacuo. The residue was purified by chromatography (SPE,DCM-MeOH 9:1) to give the title compound. LCMS RT=2.14 min.

iv) 4-{3-[(Aminocarbonyl)amino]phenyl}butyl methanesulfonate

Prepared by methods similar to those described for Example 38 iii). LCMSRT=2.65 min.

v)N-{3-[4-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)butyl]phenyl}urea

Prepared by methods similar to those described for Example 35 iv). LCMSRT=3.56 min.

vi)N-[3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)phenyl]ureaacetate

Prepared by methods similar to those described for Example 3 ii) LCMSRT=2.23 min. ES+ve m/z 494 (MH)⁺

EXAMPLE 403-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzoicacid acetate

i) 3-(4-Hydroxybut-1-ynyl)benzoic acid

Prepared by methods similar to those described for Example 35 i) LCMSRT=2.48 min.

ii) 3-(4-Hydroxybutyl)benzoic acid

Prepared by methods similar to those described for Example 35 ii). LCMSRT=2.48 min.

iii) Benzyl 3-(4-hydroxybutyl)benzoate

A solution of 3-(4-hydroxybutyl)benzoic acid (100 mg) in dry DMF (10 ml)was treated with diisopropylethylamine (0.134 ml) and benzyl bromide(106 mg) and the reaction mixture was stirred for 65 h. The reactionmixture was partitioned between EtOAc and water. The organic phase waswashed with sat. NH₄Cl_((aq)), dried (MgSO₄) and concentrated in vacuo.The residue was purified by chromatography (SPE, gradient Cyclohexane tocyclohexane-EtOAc 1:1) to give the title compound LCMS RT=3.38 min.

iv) Benzyl 3-(4-bromobutyl)benzoate

Prepared by methods similar to those described for Example 35 iii) LCMSRT=4.01 min.

v) Benzyl3-[4-(4-[2-[(5R)-5-(2,2dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)butyl]benzoate

Prepared by methods similar to those described for Example 35 iv) LCMSRT=4.10 min.

vi)3-{4-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]butyl}benzoicacid

Prepared by methods similar to those described for Example 1 xiv). LCMSRT=2.89 min.

vii)3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzoicacid acetate

Prepared by methods similar to those described for Example 1 xv). LCMSRT=2.58 min; ES+ve m/z 479 (MH)⁺

EXAMPLE 413-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzonitrileacetate

i) 3-(4-Bromobutyl)benzonitrile

Prepared by methods similar to those described for Example 35iii) from3-(4-hydroxybutyl)benzonitrile [Hua Hsueh Hsueh Pao 1964, 30, 166-75.CAN 61:47615] LCMS RT=3.50 min.

ii)3-[4-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)butyl]benzonitrile

Prepared by methods similar to those described for Example 35 iv) LCMSRT=3.74 min.

iii)3-{4-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]butyl}benzonitrile

Prepared by methods similar to those described for Example 1 xiv). LCMSRT=2.86 min.

iv)3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzonitrileacetate

Prepared by methods similar to those described for Example 1 xv). LCMSRT=2.64 min; ES+ve m/z 461 (MH)⁺

EXAMPLE 423-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzamideacetate

i)3-{4-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]butyl}benzamide

Prepared by methods similar to those described for Example 10 ii). LCMSRT=2.63 min.

ii)3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzamideacetate

Prepared by methods similar to those described for Example 1 xv) LCMSRT=2.34 min; ES+ve m/z 479 (MH)⁺

EXAMPLE 433′-](2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-1,1′-biphenyl-3-carboxylicacid acetate

i) Methyl3′-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-1,1′-biphenyl-3-carboxylate

A mixture of(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one{Example 6 i)} (150 mg), 3-(methoxycarbonyl)phenylboronic acid (47 mg),tetrakis(triphenylphosphine)palladium (0) (6 mg) and 2N sodium carbonate(7 mL) in dimethoxyethane (10 mL) was heated at 85° C. for 1 h. Thesolution was then diluted in EtOAc, washed with water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography(Biotage, 40 g) eluting with CH₂Cl₂-MeOH (200:1) to give the titlecompound (128 mg). LCMS RT=3.99 min.

ii)3′-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy]methyl)-1,1′-biphenyl-3-carboxylicacid

Prepared using methods similar to those described in Example 1 xiv) LCMSRT=2.92 min.

iii)3′-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-1,1′-biphenyl-3-carboxylicacid acetate

Prepared using methods similar to those described in Example 1 xv) LCMSRT=2.78 min, ES+ve 558 (MH)⁺

EXAMPLE 44N-Butyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamideacetate

i)N-Butyl-3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzamide

Prepared using methods similar to those described in Example 28 x). LCMSRT=3.42 min

ii)N-Butyl-3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzamide

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.65 min

iii)N-Butyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamideacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.41 min ES+ve 537 (MH)⁺

EXAMPLE 453-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-pentylbenzamideacetate

i)3-{[2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-pentylbenzamide

Prepared using methods similar to those described in Example 28 x). LCMSRT=3.55 min

ii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-pentlbenzamide

Prepared using methods similar to those described in Example 1 xiv) LCMSRT=2.76 min

iii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-pentylbenzamideacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.51 min ES+ve 551 (MH)⁺

EXAMPLE 463-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isobutylbenzamideacetate

i)3-{[2-(4-[2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-isobutyl]benzamide

Prepared using methods similar to those described in Example 28 x). LCMSRT=3.42 min

ii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-isobutylbenzamide

Prepared using methods similar to those described in Example 1 xiv) LCMSRT=2.72 min

iii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isobutylbenzamideacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.38 min ES+ve 537 (MH)⁺

EXAMPLE 473-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopentylbenzamideacetate

i)3-{[2-(4-[2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}-N-isopentylbenzamide

Prepared using methods similar to those described in Example 28 x). LCMSRT=3.52 min

ii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N-isopentylbenzamide

Prepared using methods similar to those described in Example 1 xiv).LCMS RT=2.78 min

iii)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopentylbenzamideacetate

Prepared using methods similar to those described in Example 1 xv). LCMSRT=2.52 min ES+ve 551 (MH)⁺

EXAMPLE 483-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide

i) 2-[(3-Cyanobenzyl)oxy]ethyl methanesulfonate

To a solution of 3-[(2-hydroxyethoxy)methyl]benzonitrile (example 28vi)(6.00 g) and diisopropylethylamine (11.8 ml) in dichloromethane (100 ml)at 0° C. was added methanesulphonyl chloride (3.14 ml) dropwise and themixture allowed to stir for 2 h. The resultant mixture was partitionedbetween dichloromethane and saturated sodium hydrogen carbonate. Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give thetitle compound (8.5 g). LCMS RT=2.58 min.

ii) 3-[(2-Bromoethoxy)methyl]benzonitrile

A mixture of 2-[(3-cyanobenzyl)oxy]ethyl methanesulfonate (6.83 g) andtetrabutylammonium bromide (17.2 g) in acetonitrile (250 ml) was heatedat 50° C. for 18 h. Further tetrabutylammonium bromide (5.00 g) wasadded and the mixture heated at 50° C. for 7 h. The solvent was removedin vacuo and the residue partitioned between ethyl acetate and water.The organic phase was washed with brine, dried (MgSO₄), and concentratedin vacuo to give the title compound (5.51 g). LCMS RT=3.05 min.

iii) 3-({2-[4-(2-Hydroxyethyl)phenoxy]ethoxy}methyl)benzonitrile

A mixture of 3-[(2-bromoethoxy)methyl]benzonitrile (5.00 g),2-(4-hydroxyphenyl)ethanol (3.45 g), and potassium carbonate (5.76 g) inN,N-dimethylformamide (30 ml) was heated at 60° C. for 66 h. The mixturewas allowed to cool and partitioned between ethyl acetate and 2N HCl.The aqueous phase was extracted with ethyl acetate and the combinedorganic phase washed with 2N NaOH, brine, dried (MgSO₄) and concentratedin vacuo. The residue was purified by chromatography (SPE, eluted withgradient between cyclohexane and 80% EtOAc in cyclohexane) to give thetitle compound (5.05 g). LCMS RT=2.96 min.

iv) 2-(4-{2-[(3-Cyanobenzyl)oxy]ethoxy}phenyl)ethyl methanesulfonate

To a solution of3-({2-[4-(2-hydroxyethyl)phenoxy]ethoxy}methyl)benzonitrile (5.04 g) anddiisopropylethylamine (5.94 ml) in dichloromethane (50 ml) at 0° C. wasadded methanesulphonyl chloride (1.58 ml) dropwise and the mixtureallowed to stir for 2 h. The resultant mixture was partitioned betweendichloromethane and saturated sodium hydrogen carbonate. The organicphase was dried (MgSO₄) and concentrated in vacuo to give the titlecompound (6.02 g). LCMS RT=3.22 min.

v) 3-({2-[4-(2-Bromoethyl)phenoxy]ethoxy}methyl)benzonitrile

A mixture of 2-(4-{2-[(3-cyanobenzyl)oxy]ethoxy}phenyl)ethylmethanesulfonate (6.02 g) and tetrabutylammonium bromide (15.5 g) inacetonitrile (150 ml) was heated at 50° C. for 18 h. The solvent wasremoved in vacuo and the residue partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried (MgSO₄), andconcentrated in vacuo to give the title compound (5.48 g). LCMS RT=3.60min.

vi)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzonitrile

A solution of(1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (4.42 g) inN,N-dimethylformamide (150 mL) was treated with diisopropylethylamine(6.89 ml) and 3-({2-[4-(2-bromoethyl)phenoxy]ethoxy}methyl) (5.48 g).The reaction mixture was heated at 50° C. for 17 h. The reaction mixturewas concentrated in vacuo and partitioned between ethyl acetate andwater. The aqueous phase was extracted with ethyl acetate and thecombined organic phase washed with brine, dried (MgSO₄) and concentratedin vacuo. The residue was purified by chromatography (SPE, eluted withgradient between dichloromethane and 6% methanol in dichloromethane) togive the title compound (4.6 g). LCMS RT=2.67 min.

vii)3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzamide

A solution of3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzonitrile(4.6 g) in tetrahydrofuran (70 ml) was treated with potassiumtrimethylsilanoate (9.32 g) and heated at 70° C. for 71 h. The reactionmixture was concentrated in vacuo and partitioned between ethyl acetateand water. The aqueous phase was extracted with ethyl acetate and thecombined organic phase washed with brine, dried (MgSO₄) and concentratedin vacuo. The residue was purified by chromatography (SPE, eluted with agradient between dichloromethane and 10% methanol in dichloromethane) togive the title compound (1.01 g). LCMS RT=2.42 min.

viii)3-[(2-{4-[2-({(2R-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzamidewas dissolved in methanol and applied to a SCX-2 cartridge. Elutionusing 1% ammonia in methanol, removal of the solvent in vacuo, andpurification by chromatography (SPE, eluted with a gradient between 10%methanol in dichloromethane and 16% methanol in dichloromethane) gavethe title compound (0.57 g). LCMS RT=2.11 min ES+ve m/z 481 (MH)⁺

EXAMPLE 49

i)3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamidehydrochloride salt

To a solution of3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide(25 mg) in iso-propanol (0.45 ml) was added hydrochloric acid (12M, 5.1μl). A heat-cool cycle was applied between 0° C. and 40° C., and themixture agitated for 90 h. The precipitate was filtered to give thetitle compound (20 mg). Mp 151- 153° C.; ¹H NMR δ (CD₃OD, 400 MHz) 7.88(1H, br s), 7.78 (1H, br d, J 8 Hz), 7.55 (1H, d, J 8 Hz), 7.43 (1H, t,J 8 Hz), 7.34 (1H, br d, J 2 Hz), 7.22-7.13 (3H, m), 6.92 (2H, br d, J 8Hz), 6.77 (1H, d, J 8 Hz), 4.65 (4H, d, J 7 Hz), 4.16-4.11 (2H, br t, J4 Hz), 3.87-3.81 (2H, br t, J 4 Hz), 3.27-3.20 (2H, br t, J 8 Hz),2.98-2.90 (2H, m).

Biological Activity

The potencies of the aforementioned compounds were determined using frogmelanophores transfected with the human beta 2 adrenoreceptor. The cellswere incubated with melatonin to induce pigment aggregation. Pigmentdispersal was induced by compounds acting on the human beta 2adrenoreceptor. The beta 2 agonist activity of test compounds wasassessed by their ability to induce a change in light transmittanceacross a melanophore monolayer (a consequence of pigment dispersal). Atthe human beta 2 adrenoreceptor, compounds of examples 1-47 had IC₅₀values below 1 μM.

Potency at other beta adrenoreceptor subtypes was determined usingchinese hamster ovary cells transfected with either the human beta 1adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity wasassessed by measuring changes in intracellular cyclic AMP.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A compound of formula (I):

or a salt, or solvate thereof, wherein: m is an integer of from 2 to 4;p is an integer of from 1 to 4, preferably 1; Z is O or CH₂— R¹ isselected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, cyano, nitro,halo, C₁₋₆haloalkyl, XCO₂R⁸, —XC(O)NR⁷R⁸, —XNR⁶C(O)R⁷, —XNR⁶C(O)NR⁷R⁸,—XNR⁶C(O)NC(O)NR⁷R⁸, —XNR⁶SO₂R⁷, —XSO₂NR⁹R¹⁰, —XNR⁶SO₂NR⁹R¹⁰, XSR⁶,XSOR⁶, XSO₂R⁶, —XNR⁷R⁸, —XNR⁶C(O)OR⁷, or R¹ is selected from —X-aryl,—X-hetaryl, or —X-(aryloxy), each optionally substituted by 1 or 2groups independently selected from hydroxy, C₁₋₆alkoxy, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, —NR⁶C(O)R⁷, SR⁶, SOR⁶, —SO₂R⁶, —SO₂NR⁹R¹⁰, —CO₂R⁸,—NR⁷R⁸, or hetaryl optionally substituted by 1 or 2 groups independentlyselected from hydroxy, C₁₋₆alkoxy, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl; Xis —(CH₂)_(q)— or C₂₋₆ alkenylene; q is an integer from 0 to 6,preferably 0 to 4; R⁶ and R⁷ are independently selected from hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, hetaryl, hetaryl(C₁₋₆alkyl)- andaryl(C₁₋₆alkyl)- and R⁶ and R⁷ are each independently optionallysubstituted by 1 or 2 groups independently selected from halo,C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl,—NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl), —SO₂(aryl), —CO₂H, and—CO₂(C₁₋₄alkyl), —NH₂, —NH(C₁₋₆alkyl), aryl(C₁₋₆alkyl)-,aryl(C₂₋₆alkenyl)-, aryl(C₂₋₆alkynyl)—, hetaryl(C₁₋₆alkyl)-, —NHSO₂aryl,—NH(hetarylC₁₋₆alkyl), —NHSO₂hetaryl, —NHSO₂(C₁₋₆alkyl), —NHC(O)aryl, or—NHC(O)hetaryl; or where R¹ is —XNR⁶C(O)OR⁷, R⁶ and R⁷ may, togetherwith the —NC(O)O— portion of the group R¹ to which they are bonded, forma saturated or unsaturated ring, preferably a 5-, 6-, or 7-memberedring, for example an oxazolidine ring, such as oxazolidine-2,4-dione, orwhere R¹ is —XNR⁶C(O)NR⁷R⁸, R⁶ and R⁷ may, together with the —NC(O)N—portion of the group R¹ to which they are bonded, form a saturated orunsaturated ring, preferably a 5-, 6-, or 7-membered ring, for examplean imidazolidine ring, such as imidazolidine-2,4-dione; R⁸ is selectedfrom hydrogen, C₁₋₆alkyl and C₃₋₇ cycloalkyl; or R⁷ and R⁸, togetherwith the nitrogen atom to which they are bonded, form a 5-, 6- or7-membered nitrogen-containing ring; R⁹ and R¹⁰ are independentlyselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, CO₂(C₁₋₄alkyl), aryl,hetaryl, hetaryl(C₁₋₆alkyl)- and aryl(C₁₋₆alkyl)-, or R⁹ and R¹⁰,together with the nitrogen to which they are bonded, form a 5-, 6-, or7-membered nitrogen containing ring; and R⁹ and R¹⁰ are each optionallysubstituted by one or two groups independently selected from halo,C₁₋₆alkyl, and C₃₋₇cycloalkyl, C₁₋₆haloalkyl; R² is selected fromhydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo, aryl, aryl(C₁₋₆alkyl)-,C₁₋₆haloalkoxy, and C₁₋₆haloalkyl; R³ is selected from hydrogen,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo, aryl, aryl(C₁₋₆alkyl)-,C₁₋₆haloalkoxy, and C₁₋₆haloalkyl; and R⁴ and R⁵ are independentlyselected from hydrogen and C₁₋₄ alkyl with the proviso that the totalnumber of carbon atoms in R⁴ and R⁵ is not more than
 4. 2. A compoundaccording to claim 1 wherein R¹ is selected from hydrogen, C₁₋₆alkyl,hydroxy, cyano, nitro, halo, C₁₋₆haloalkyl, XCO₂R⁸, —XC(O)NR⁷R⁸,—XNR⁶C(O)R⁷, —XNR⁶C(O)NR⁷R⁸, —XNR⁶C(O)NC(O)NR⁷R⁸, —XNR⁶SO₂R⁷,—XSO₂NR⁹R¹⁰, —XSR6, —XSOR⁶, —XSO₂R⁶, —XNR⁷R⁸, —XNR⁶C(O)OR⁷, or R¹ isselected from —X-aryl, —X-hetaryl, or —X-(aryloxy), each optionallysubstituted by 1 or 2 groups independently selected from hydroxy,C₁₋₆alkoxy, halo, C₁₋₆alkyl, C1-6haloalkyl, —NR⁶C(O)R⁷, SR⁶, SOR⁶,—SO₂R⁶, —SO₂NR⁹R¹⁰, —CO₂R⁸, —NR⁷R⁸, or hetaryl optionally substituted by1 or 2 groups independently selected from hydroxy, C₁₋₆alkoxy, halo,C₁₋₆alkyl, or C₁₋₆haloalkyl; wherein R⁶, R⁷, R⁸, are as defined in claim1 and R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, aryl, hetaryl, hetaryl(C₁₋₆alkyl)- and aryl(C₁₋₆alkyl)-,or R⁹ and R¹⁰, together with the nitrogen to which they are bonded, forma 5-, 6-, or 7-membered nitrogen containing ring; and R⁹ and R¹⁰ areeach optionally substituted by one or two groups independently selectedfrom halo, C₁₋₆alkyl, and C₃₋₇cycloalkyl, C₁₋₆haloalkyl.
 3. A compoundaccording to claim 1 wherein the group R¹ is selected from hydroxy,—XC(O)NR⁷R⁸, and —XSO₂NR⁹R¹⁰.
 4. A compound according to claim 1 whereinthe compound is selected from the group consisting of:N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}urea;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}dicarbonimidic diamide;4-((1R)-2-{[2-(4-{2-[(3-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;2-(Hydroxymethyl)-4-((1R)-1-hydroxy-2-{[2-(4-{2-[(3-methylbenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)phenol;4-((1R)-2-{[2-(4-{2-[(3-Chlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}acetamide;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}nicotinamide;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-2-furamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzonitrile;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}methanesulfonamide;4-{(1R)-2-[(2-{4-[2-)Benzyloxy]ethoxy]phenyl}ethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}-N′-phenylurea;4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(3-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;4-{(1R)-2-[((1S)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;4-{(1R)-2-[((1R)-2-{4-[2-(Benzyloxy)ethoxy]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzenesulfonamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzoicacid;4-((1R)-2-{[2-(4-{2-[(4-Fluorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;4-((1R)-2-{[2-(4-{2-[(2,6-Dichlorobenzyl)oxy]ethoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;N-{3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamide,N-(tert-butoxycarbonyl)-N′-{3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]phenyl}sulfamide;4-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;4-[(1R)-2-({2-[4-(2-{[3-(Cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-isopropoxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;4-((1R)-1-Hydroxy-2-{[2-(4-{2-[(4-hydroxybenzyl)oxy]ethoxy}phenyl)ethyl]amino}ethyl)-2-(hydroxymethyl)phenol;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopropylbenzamide;N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;N-Cyclohexyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzenesulfonamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-methylbenzenesulfonamide;4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenol;4-[(1R)-1-Hydroxy-2-({2-[4-(2-{[3-(isopropylsulfonyl)benzyl]oxy}ethoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenol;2-(Hydroxymethyl)-4-[(1R)-1-hydroxy-2-({2-[4-(4-phenylbutoxy)phenyl]ethyl}amino)ethyl]phenol;4-{(1R)-1-Hydroxy-2-[(2-{4-[4-(3-hydroxyphenyl)butoxy]phenyl}ethyl)amino]ethyl}-2-(hydroxymethyl)phenol;4-((1R)-2-{[2-(4-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}phenyl)ethyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;4-{(1R)-2-[(2-{4-[4-(2,6-Dichlorophenyl)butoxy]phenyl}ethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzenesulfonamideN-[3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)phenyl]urea;3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzoicacid;3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzonitrile;3-(4-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)benzamide;3′-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-1,1′-biphenyl-3-carboxylicacid;N-Butyl-3-[(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-pentylbenzamide;3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isobutylbenzamide;and3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]-N-isopentylbenzamide;or a salt thereof, or a solvate thereof.
 5. A compound according toclaim 1 which is3-[(2-{4-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethoxy)methyl]benzamide;or a salt thereof, or a solvate thereof.
 6. A method for the treatmentof a clinical condition in a mammal, for which a selectiveβ₂-adrenoreceptor agonist is indicated, wherein said clinical conditionis selected from the group consisting of asthma, chronic obstructivepulmonary diseases respiratory tract infection, and upper respiratorytract disease, which comprises administrating a therapeuticallyeffective amount of a compound according to claim 1 or apharmaceutically acceptable salt, or solvate thereof.
 7. Apharmaceutical formulation comprising a compound according to claim 1,or a pharmaceutically acceptable salt, or solvate thereof, and apharmaceutically acceptable carrier or excipient, and optionally one ormore other therapeutic ingredients.
 8. A process for the preparation ofa compound of formula (I), according to claim 1, or a salt, or solvatethereof, wherein said process is selected from the group consisting of(a), (b), (c) and (d): (a) deprotecting a protected intermediate offormula (II):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, Z, m, and pare as defined for the compound of formula (I), and R¹¹, R¹², R¹³ andR¹⁴ are each independently either hydrogen or a protecting groupprovided that at least one of R¹¹, R¹², R¹³ and R¹⁴ is a protectinggroup; (b) alkylating an amine of formula (XIII)

wherein R¹¹, R¹², R¹³ and R¹⁴ are each independently either hydrogen ora protecting group, with a compound of formula (XIV):

wherein R¹, R², R³, R⁴, R⁵, Z, m, and p are as defined for the compoundof formula (I) and L¹ is a leaving group; (c) reacting a compound offormula (XV):

wherein R¹¹ R¹² and R¹⁴ are as hereinbefore defined and L³ is a leavinggroup, with an amine of formula (XVI):

(d) reacting a compound of formula (XIII):

wherein R¹¹, R¹², R¹³ and R¹⁴ are each independently either hydrogen ora protecting group provided that at least one of R¹¹, R¹², R¹³ and R¹⁴is a protecting group with a compound of formula (XVII):

wherein R¹, R², R³, R⁴, Z, m, and p are as defined for the compounds offormula (I), under conditions suitable to effect reductive amination,wherein processes (a), (b), (c), or (d) may optionally be followed byone or more of the following steps in any order: (i) optional removal ofany protecting groups; (ii) optional separation of an enantiomer from amixture of enantiomers; (iii) optional conversion of the product to acorresponding salt, or solvate thereof.
 9. A method according to claim6, wherein the mammal is a human.
 10. A compound according to claim 1wherein R¹ is —XC(O)NR⁷R⁸.